Therapeutic Mechanisms of Phenothiazine Drugs: A Mini-Review of Advances in Cancer Treatment and Antibiotic Resistance

Xuewei Zou; Bai Xie

doi:10.5812/ijpr-157923

https://doi.org/10.5812/ijpr-157923

Therapeutic Mechanisms of Phenothiazine Drugs: A Mini-Review of Advances in Cancer Treatment and Antibiotic Resistance

authors:

Xuewei Zou ^{1
, *} , Bai Xie ¹

1 College of Veterinary Medicine of Yangzhou University, Yangzhou, China

IJ Pharmaceutical Research: Vol.24, issue 1; e157923

published online: February 8, 2025

article type: Review Article

received: November 19, 2024

revised: December 22, 2024

accepted: December 31, 2024

How To Cite? Zou X, Xie B. Therapeutic Mechanisms of Phenothiazine Drugs: A Mini-Review of Advances in Cancer Treatment and Antibiotic Resistance. Iran J Pharm Res. 2025;24(1):e157923. https://doi.org/10.5812/ijpr-157923.

Abstract

Context:

Cancer and antibiotic resistance are critical global health challenges. Phenothiazines, initially developed as antipsychotics, have demonstrated diverse biological activities, including antitumor, antibacterial, and antioxidant effects. Advances in phenothiazine synthesis have produced derivatives with broader therapeutic potential by modulating receptors, ion channels, and inducing lysosomal cell death. This review explores the therapeutic potential of phenothiazines in oncology and infectious disease management, focusing on their mechanisms of action and future clinical applications.

Evidence Acquisition:

This narrative review synthesizes insights from relevant preclinical studies on phenothiazines' applications in oncology and infectious diseases. Mechanistic pathways and experimental outcomes were analyzed to highlight therapeutic potentials and limitations.

Results:

Phenothiazines demonstrate significant potential in oncology by inhibiting tumor growth via apoptosis induction, pathway modulation (e.g., PDK1/Akt, MAPK/ERK1/2, and Akt/mTOR), angiogenesis suppression through vascular endothelial growth factor (VEGF) production inhibition, and enhancing the effectiveness of monoclonal antibody therapies. They disrupt key cancer-promoting pathways and induce lysosomal cell death. Beyond oncology, phenothiazines exhibit antibacterial activity, targeting efflux pumps (Eps) and restoring antibiotic susceptibility in multidrug-resistant (MDR) pathogens. These multifaceted actions position phenothiazines as promising agents for combination therapies in cancer treatment and antibiotic-resistant infections.

Conclusions:

Phenothiazines hold promise as adjuvants in cancer and antibiotic resistance management. Further research should focus on optimizing their pharmacological profiles, elucidating molecular mechanisms, and validating their efficacy through clinical trials.

Keywords

Phenothiazines Therapeutic Mechanisms Anticancer Activity Antibiotic Resistance Combination Therapy

1. Context

Phenothiazines have demonstrated remarkable therapeutic versatility since their introduction in the 1950s. Initially recognized for their antipsychotic properties, particularly chlorpromazine's impact on schizophrenia treatment through D2 receptor antagonism, their applications extend to diverse conditions, including acute intermittent porphyria, methemoglobinemia, anxiety, and nausea. This broad efficacy stems from their unique chemical structure, enabling interactions with a wide range of biological targets (1).

Phenothiazines are a class of cationic and amphiphilic compounds featuring two phenyl rings and a thiazine ring containing sulfur and nitrogen, with an alkyl bridge connected to the nitrogen atom in the thiazine ring (2). The substituents at position C-2 of the tricyclic phenothiazine ring and the length of the alkyl bridge connecting the nitrogen atom at position 10 (N-10) to the terminal amine group significantly influence their anticancer efficacy (3, 4). The type of substituents in the phenothiazine ring, more than the side chain nature, plays a crucial role in their effectiveness against cancer cells (5). Modifications to the phenothiazine ring have led to derivatives such as benzo[α]phenothiazines and azaphenothiazines, which exhibit notable anticancer effects on various cell lines in vitro (6, 7).

Primarily, phenothiazines are neuroleptic medications used to treat schizophrenia and other psychiatric disorders (8). The first derivative, chlorpromazine, synthesized in the early 1950s by Rhone-Poulenc during the search for antihistaminic drugs, revolutionized psychopharmacology with its antipsychotic properties (9). Phenothiazines also serve as potent antiemetics (10). Although their exact mechanism of action is not fully elucidated, they primarily inhibit dopamine receptors in the mesolimbic pathway, particularly the D2 receptor, counteracting dopamine hyperactivity and reducing positive schizophrenia symptoms such as delusions and hallucinations (11). They also interact with adrenergic, H1 histaminergic, and serotoninergic receptors (12), modulate GABA-mediated inhibitory synaptic transmission in cultured hippocampal neurons (13), and inhibit voltage-gated Kv1.3 channels in T lymphocytes (14). However, their use is associated with side effects such as extrapyramidal symptoms and cardiac arrhythmias (15, 16), prompting the development of second-generation antipsychotics.

Structurally, phenothiazines consist of a 1,4-thiazine nucleus connected to two benzene rings (Figure 1). The substituents at positions 2 and 10 of the benzothiazine structure influence pharmacological activity (17). Based on the ligand at position 10, phenothiazines are classified as aliphatic, piperazine, or piperidine, with chlorpromazine, trifluoperazine, and thioridazine as respective examples. These substituents also affect cytotoxicity and other cellular processes. The amphiphilic nature of phenothiazines allows interaction with biological membranes, modifying their properties (18-20). Additionally, phenothiazines, as lysosomotropic compounds, accumulate in lysosomes, potentially causing lysosomal permeabilization, disruption of intracellular trafficking, and cell death (21-23). They also interfere with endocytosis; chlorpromazine and trifluoperazine inhibit dynamin- and clathrin-mediated endocytosis, enhancing the efficacy of monoclonal antibody-targeted cancer treatments by increasing protein availability for natural killer cell-mediated antibody-dependent cytotoxicity (24, 25).

Figure 1.

Structure of phenothiazine and well-known marketed phenothiazine derivatives with demonstrated anti-cancer effects

Understanding the molecular mechanisms of phenothiazines' antitumor actions is crucial for their potential repurposing as adjuvants in cancer chemotherapy. Despite extensive study, further investigation into phenothiazines’ mechanisms, particularly in combination therapies for cancer and antibiotic resistance, is essential. This review examines these therapeutic potentials, focusing on phenothiazines’ applications in oncology and infectious disease.

2. Evidence Acquisition

2.1. Combination Therapies with Phenothiazines: Recent Advances

Phenothiazines, particularly chlorpromazine, thioridazine, and promethazine, exhibit cytotoxic effects on cancer cells and modulate bacterial resistance, making them promising candidates for combination therapies. Their multi-target actions—including efflux pump (EP) inhibition, membrane destabilization, and apoptosis induction—enhance the efficacy of chemotherapy and antibiotics (26). Studies indicate that phenothiazines sensitize cancer cells to conventional drugs by inhibiting EPs such as P-glycoprotein, thereby boosting intracellular drug levels, disrupting metabolic pathways, and reducing autophagy, which collectively increase apoptosis in resistant cells (27).

Thioridazine, for example, has demonstrated synergy with carboplatin, doxorubicin, and cisplatin in resistant breast and lung cancers, highlighting its potential in treating challenging tumors (28). Phenothiazines also combat multidrug-resistant (MDR) bacteria by inhibiting bacterial EPs and enhancing antibiotic efficacy. When combined with antibiotics like ampicillin and ciprofloxacin, they restore susceptibility in MDR strains by disrupting bacterial membranes—a strategy effective against Burkholderia pseudomallei, Escherichia coli, and Staphylococcus aureus.

Although dosage optimization remains critical to minimize toxicity, ongoing research into modified derivatives and nanoparticle delivery systems may improve the safety and precision of phenothiazine-based therapies (29).

2.2. Phenothiazines and Cancer: Advances in Therapeutic Mechanisms

Phenothiazines exhibit promising antitumor effects across various cancer types through diverse mechanisms (Figure 2 and Table 1). These compounds induce cell cycle arrest and apoptosis and target critical cancer pathways, such as PI3K/AKT, mTOR, and FOXO transcription factors, thereby disrupting tumor growth and enhancing tumor sensitivity to therapies (30, 31).

Figure 2.

Summary of phenothiazines investigated for antitumor activity and their target malignancies. This figure offers a complete summary of different phenothiazines studied for their anti-cancer effects and the types of cancers they target. It outlines the particular cancers that these medications have shown effective anti-cancer effects against. Every phenothiazine is paired with its specific target cancer, demonstrating the variety of cancers that phenothiazines are able to treat.

Table 1.

Anti-tumor Activities and Mechanisms of Action of Phenothiazines Across Various Cancer Types

Phenothiazine	Cancer Types	Anti-tumor Activity	Mechanisms of Action
Chlorpromazine	Glioma, leukemia, endometrial, glioblastoma, pancreatic, hepatocellular carcinoma, oral cancer, hepatoma	Cytotoxic, induces apoptosis, inhibits cell proliferation	Inhibits cytochrome c oxidase in COX4-1 expressing cells, induces autophagic cell death, disrupts K-Ras membrane binding, promotes K-Ras cytoplasmic translocation, increases ROS, inhibits PI3K/AKT/mTOR, activates ER stress and UPR (ATF6-α)
Fluphenazine	Melanoma, colon and breast cancer, triple-negative breast cancer, ovarian carcinoma, doxorubicin-resistant colon cancer, glioblastoma	Anti-proliferative, induces apoptosis, enhances immune response, enhances drug efficacy	Induces G0/G1 arrest, mitochondrial apoptosis, DNA damage via γ-H2AX, activates caspase-3, reduces mitochondrial potential, blocks PI3K-AKT-mTOR pathways, enhances sensitivity to chemotherapy, inhibits autophagy
Thioridazine	Cervix, breast, NSCLC, ovarian, glioblastoma, colorectal, esophageal, hepatocellular carcinoma, leukemia, gastric cancer, larynx, renal, melanoma	Induces apoptosis, reduces viability, inhibits metastasis, enhances chemotherapy sensitivity	G0/G1 arrest, caspase activation, inhibition of PI3K/AKT/mTOR/p70S6K, mitochondrial apoptosis, enhances AMPK activity, increases ROS, reduces Bcl-2, activates autophagy, suppresses stemness genes
Trifluoperazine	Melanoma, triple-negative breast cancer, glioblastoma, squamous cell carcinoma, colon, osteosarcoma, hepatocellular carcinoma, larynx, renal carcinoma	Anti-proliferative, reduces viability, enhances radiation-induced cell death, mitochondrial damage	Lysosomal dysfunction, autophagy inhibition, induces G0/G1 arrest, reduces cyclin/CDK levels, interferes with Ca²⁺ signaling, activates ROS and mitophagy, enhances Bax/Bcl-2 ratio, induces apoptosis, enhances doxorubicin efficacy
Prochlorperazine	Squamous cell carcinoma, NSCLC, leukemia	Increases cancer cell death, boosts antibody efficacy, sensitizes to stress factors	Alters EGFR distribution, reduces Akt/mTOR signaling, binds KRAS GTP-binding pocket, activates p53, p21, γH2AX, enhances ROS, induces apoptosis through DNA damage and cell cycle arrest
Promethazine	Leukemia, colorectal cancer, small cell lung cancer	Cytotoxic, reduces growth, induces mitochondrial apoptosis, enhances radiation sensitivity	Activates AMPK, inhibits PI3K/AKT/mTOR, induces autophagy, triggers cell death through GPCR inhibition and JNK/c-Jun signaling, reduces cyclin levels in colorectal cancer

Abbreviations: NSCLC, non-small cell lung cancer; ROS, reactive oxygen species.

For instance, chlorpromazine has shown efficacy in glioma, endometrial cancer, and pancreatic cancer by promoting apoptosis, inhibiting cell proliferation, and blocking key signaling pathways (32, 33). It enhances autophagic cell death in glioblastoma and disrupts K-Ras binding in pancreatic cancer, promoting its cytoplasmic translocation and subsequent cell death (34). Similarly, fluphenazine is effective against melanoma, triple-negative breast cancer, and colon cancer, inducing mitochondrial apoptosis, cell cycle arrest, and disruption of the PI3K/AKT/mTOR pathways, thereby reducing tumor growth and enhancing immune responses (35, 36).

Thioridazine demonstrates potent antiproliferative effects in ovarian, lung, and cervical cancers through G0/G1 arrest, mitochondrial apoptosis, and inhibition of vascular endothelial growth factor (VEGF) and PI3K/mTOR pathways (37). Prochlorperazine enhances the efficacy of anticancer antibodies in squamous cell carcinoma by targeting EGFR distribution (25), while promethazine shows cytotoxic effects in leukemia and colorectal cancer by promoting autophagy and mitochondrial apoptosis (38, 39).

Beyond direct anticancer effects, phenothiazines modulate tumor-promoting pathways, such as tumor angiogenesis and oxidative stress. For example, they reduce VEGF production and affect angiogenesis-related signaling (40), while compounds like chlorpromazine alter oncogenic pathways in glioblastoma and endometrial cancers, impacting p53, Ras, and dopamine receptor pathways (41). Additionally, phenothiazines promote mitophagy through the AMPK/mTOR/ULK1 pathway, enhancing autophagy and mitigating mitochondrial damage in cancer cells (30). Furthermore, phenothiazines activate the Nrf2/ARE pathway, bolstering antioxidant defenses and selectively increasing cancer cell apoptosis (40). Trifluoperazine, in particular, enhances FOXO1 nuclear retention and reverses resistance mechanisms in lung adenocarcinoma by activating the KLF6/FOXO1 pathway (42).

Despite these promising preclinical results, further research is required to optimize phenothiazine derivatives for clinical application in cancer therapy, particularly to harness their broad and complex mechanisms of action across multiple tumor-promoting processes. In Table 2, we summarize studies investigating the antitumor activities of phenothiazines.

Table 2.

Studies Investigating Anti-Tumor Activities and the Relevant Mechanisms of Phenothiazines

Authors, References	Phenothiazine	Cancer Type	Anti- Tumor Activity	Mechanisms of Action
Oliva et al. (32)	Chlorpromazine	Glioma (temozolomide-resistant)	Cell cycle arrest, increased survival in mice	Inhibits cytochrome c oxidase selectively in COX4-1 expressing cells
Zhelev et al. (43)	Chlorpromazine, levomepromazine, promethazine, trifluoperazine, thioridazine	Leukemia (various)	Anti-proliferative, cytotoxic, induces apoptosis	Enhances phosphatidylserine-annexin V complexes, triggers DNA fragmentation
Cui et al. (33)	Chlorpromazine	Endometrial cancer	Reduces proliferation, migration, increases apoptosis	Upregulates PRB, PI3K/AKT pathway inhibition
Matteoni et al. (34)	Chlorpromazine	Glioblastoma	Cytotoxic autophagy, mitotic arrest	ER stress, UPR activation via ATF6-α nuclear translocation
Eisenberg et al. (44)	Chlorpromazine	Pancreatic cancer (PANC-1)	Inhibits wound healing and colony formation	Disrupts K-Ras membrane binding, promoting its cytoplasmic translocation and inducing cell death
Klutzny et al. (45)	Fluphenazine	Colon and breast cancer	Anti-proliferative via cell cycle arrest	Inhibits acid sphingomyelinase, activates hypoxia stress pathways
Xi et al. (35)	Fluphenazine	Melanoma	Reduces growth, boosts immune response	G0/G1 arrest, mitochondrial apoptosis, DNA damage via γ-H2AX
Xu et al. (46)	Fluphenazine	Triple-negative breast cancer	Inhibits metastasis in brain and lungs	Blocks PI3K-AKT-mTOR pathways, reduces mitochondrial potential
Heitmann et al. (47)	Thioridazine, fluphenazine, trifluoperazine	Cervix, breast, NSCLC	Sensitizes cells to stress factors	Inhibits annexin-mediated repair, decreases membrane fluidity
Chew et al. (25)	Prochlorperazine	Squamous cell carcinoma	Boosts efficacy of anti-cancer antibodies	Alters EGFR distribution, reduces Akt/mTOR signaling
Sad et al. (48)	Prochlorperazine	NSCLC	Increases cancer cell death and survival rates in mice	Binds KRAS GTP-binding pocket, keeping mutant K-Ras in inactive form; with radiation, activates p-ATM, p53, p21, and γH2AX, promoting cell cycle arrest and apoptosis
Medeiros et al. (38)	Promethazine	Leukemia	Cytotoxic via autophagy	Activates AMPK, inhibits PI3K/AKT/mTOR pathway
Tan et al. (39)	Promethazine	Colorectal cancer	Suppresses growth, induces mitochondrial apoptosis	PI3K/AKT pathway inhibition
Jahchan et al. (49)	Promethazine	Small cell lung cancer	Reduces growth, triggers cell death	Inhibits GPCRs, activates JNK/c-Jun signaling
Kang et al. (50)	Thioridazine	Cervical, endometrial	Apoptosis induction	G1 arrest, PI3K/Akt/mTOR/p70S6K inhibition
Park et al. (51)	Thioridazine	Ovarian cancer	Reduces angiogenesis	Blocks VEGFR-2/PI3K/mTOR pathway
Song et al. (52)	Thioridazine	Triple-negative breast cancer	Inhibits growth and migration	PI3K/Akt/mTOR/p70S6K inhibition, G1 arrest
Cheng et al. (53)	Thioridazine	Glioblastoma	Autophagy induction	Enhances AMPK activity, regulates VEGFR-2
Gil-Ad et al. (54)	Thioridazine	Melanoma	Potent anti-proliferative effects	DNA fragmentation, caspase-3 upregulation
Zhang et al. (55)	Trifluoperazine	Melanoma	Reduces viability, extends survival in mice	Lysosomal damage, autophagic flux inhibition
Feng et al. (56)	Trifluoperazine	Triple-negative breast cancer	Inhibits cell proliferation	Reduces cyclinD1/CDK4, cyclin E/CDK2 levels
Zhang et al. (57)	Trifluoperazine	Glioblastoma	Enhances sensitivity to radiotherapy	Inhibits autophagy, reduces DNA repair proteins
Choi et al. (58)	Fluphenazine, chlorpromazine, trifluoperazine, thioridazine	Ovarian carcinoma	Inhibits tumor growth	Reduces Akt phosphorylation, suppresses PDK1 kinase activity
Kang et al. (59)	Trifluoperazine	Glioblastoma	Time- and dose-dependent cytotoxicity, blocks growth and spread	Induces sustained Ca²⁺ release via IP3R by binding CaM2, enhancing responsiveness in glioblastoma cells
Sroda-Pomianek et al. (36)	Fluphenazine	Doxorubicin-resistant colon cancer	Enhances doxorubicin efficacy	Lowers ABCB1 and COX-2 expression, increases Bax/Bcl-2 ratio for apoptosis
Gangopadhyay et al. (60)	Trifluoperazine	Larynx, melanoma	Enhances radiation-induced death	Interferes with Ca²⁺ signaling, induces apoptosis
Colturato-Kido et al. (61)	Thioridazine	Acute lymphoblastic leukemia	Programmed cell death induction	Increases NOXA/MCL-1 ratio, AMPK/PI3K/AKT/mTOR inhibition
Li et al. (62)	Thioridazine	Esophageal carcinoma	Reduces viability with radiation	G0/G1 arrest, caspase activation, Bcl-2 downregulation
Shen et al. (63)	Thioridazine	Lung, ovary	Enhances cisplatin chemotherapy	Mitochondrial apoptosis, reduces Bcl-2
El-Sayed Ibrahim et al. (40)	Thioridazine	Hepatocellular carcinoma (HepG2)	Reduces cell proliferation and increases ROS	Downregulates PI3K/AKT and SIRT1/NRF2 expression, lowers VEGF levels, raises oxidative stress
Min et al. (64)	Thioridazine	Renal carcinoma, breast carcinoma, glioma	Induces apoptosis, enhances TRAIL sensitivity	Decreases c-FLIP(L) and Mcl-1 via proteasome activity, suppresses Akt pathway, increases ROS in renal carcinoma cells
Qian et al. (37)	Thioridazine	Human lung and ovary cancers	Enhances cisplatin efficacy, induces apoptosis	Causes mitochondrial-dependent apoptosis via G0/G1 arrest, activates caspase 9, increases Bax, decreases Bcl-2
Seervi et al. (65)	Thioridazine	Cervical, fibroblast	Bax-Bak dependent apoptosis	ROS increase, ER stress induc
Zhang et al. (66)	Thioridazine	Colorectal cancer	Reduces growth and spread of CSCs	Increases Bax, caspase-3, decreases Bcl-2
Mu et al. (67)	Thioridazine	Gastric cancer	Cytotoxicity and colony suppression	Caspase-dependent apoptosis, mitochondrial pathway activatio
Chen et al. (68)	Thioridazine	Hepatocellular carcinoma	Induces Ca²⁺-independent cell death	Activates Ca²⁺ signaling via PKC-responsive pathways
Moraes et al. (69)	Thioridazine	Leukemia	Selective leukemia cell apoptosis	Increases cytosolic Ca²⁺, caspase 9/3 activation, ER stress
Shin et al. (70)	Chlorpromazine	Glioma	Inhibits growth, colony survival	Autophagic cell death, PI3K/AKT/mTOR inhibition
Jhou et al. (41)	Chlorpromazine	Oral cancer	Growth suppression, apoptosis	Death receptor and mitochondrial pathway activation
Goyette et al. (71)	Thioridazine, fluphenazine, trifluoperazine	Triple-negative breast cancer	Reduces invasion, proliferation, increases apoptosis	Decreases PI3K/AKT/mTOR and ERK s
Seo et al. (72, 73)	Thioridazine, curcumin	Head, neck, breast, glioma	Induces cell death in combination	Boosts PSMA5 expression, decreases c-FLIP, Mcl-1
Nagel et al. (74)	Mepazine, thioridazine, promazine	Diffuse large B cell lymphoma	Selective cytotoxicity in ABC-DLBCL	Inhibits MALT1, reduces viabilit
Lu et al. (75)	Thioridazine	Hepatocellular carcinoma	Decreases viability, migration	G0/G1 arrest, stemness gene inhibitio
Spengler et al. (76)	Thioridazine	MDR lymphoma	Promotes apoptosis	ABCB1 transporter inhibition
Antherieu et al. (77)	Chlorpromazine	Hepatoma	Induces oxidative stress	Alters bile acid transport and CYP8B1 expression
Yue et al. (78)	Thioridazine	Lung cancer stem cells	Reduces sphere formation	Decreases Akt phosphorylation, affects stem cell propertie
Dos Santos et al. (79)	Methylene blue PDT	Breast adenocarcinoma	Significant cancer cell destruction	Oxidative damage, autophagy induction
Harris et al. (80)	Chlorpromazine	Hepatocellular carcinoma	Decreases cell viability, increases ROS	Early apoptosis induction
Shen et al. (30)	Trifluoperazine	Osteosarcoma	Suppresses proliferation	ROS accumulation, mitochondrial damage, mitophagy induction
Jiang et al. (42)	Trifluoperazine	Hepatocellular carcinoma	Reduces viability, enhances apoptosis	Enhances Bax/Bcl-2 ratio, FOXO1 nuclear localization

Abbreviations: NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species; PSMA5, proteasome subunit alpha 5; COX-2, cyclooxygenase-2; ABC, ATP-binding cassette.

2.3. Phenothiazines Induce Cell Cycle Arrest and Apoptosis in Cancer Cells

Phenothiazines effectively induce cell cycle arrest and apoptosis across diverse cancer types. Fluphenazine and trifluoperazine, for instance, suppress metastasis in melanoma by causing G0/G1 phase arrest and initiating mitochondria-mediated apoptosis. In melanoma, the cyclin D–CDK4/6 pathway, frequently overactivated in metastatic cases, drives G1-S phase transition and cellular proliferation, while the RAS/RAF/MEK/MAPK pathway further amplifies cyclin D1 expression, sustaining this cycle (35, 81, 82). Trifluoperazine disrupts these processes by downregulating cyclins D and E, CDK2, CDK4, and c-Myc, while upregulating p21 and p27, leading to G0/G1 arrest and diminished tumor growth. Similarly, in hepatocellular carcinoma (HCC), trifluoperazine induces G0/G1 arrest and apoptosis by increasing the Bax/Bcl-2 ratio, effectively reducing cell viability (42, 81).

Moreover, novel phenothiazine derivatives demonstrate antiproliferative effects in lung and pancreatic cancer cell lines by inducing G0/G1 phase arrest and reducing S and G2/M phase proportions, highlighting their ability to impair cell cycle progression and promote apoptosis. These findings underscore the potential of phenothiazines as therapeutic agents targeting cell cycle dysregulation in cancer (83).

2.4. Phenothiazines Modulate Forkhead Box O Factors to Induce Cell Cycle Arrest and Apoptosis

Forkhead box O (FOXO) proteins, including FOXO1, FOXO3, FOXO4, and FOXO6, function as tumor suppressors by regulating cell cycle arrest, DNA repair, and apoptosis through pathways involving cyclins, Bcl-6, Fas ligand (FasL), and TRAIL (84). Trifluoperazine, a phenothiazine derivative, enhances FOXO1 nuclear retention and counters AKT-driven resistance to erlotinib by activating the KLF6/FOXO1 signaling pathway in lung adenocarcinoma. This is linked to its inhibition of calmodulin, which facilitates FOXO1 nuclear relocalization (85). In hepatocellular carcinoma, trifluoperazine increases FOXO1 nuclear expression, elevating Bax levels and reducing Bcl-2, thereby raising the Bax/Bcl-2 ratio to promote apoptosis. Similarly, AKT inhibition triggers FOXO3a nuclear translocation and acetylation, forming a transcriptional complex that upregulates CDK6, contributing to intrinsic resistance to AKT inhibitors (AKTi) (42). Targeting the FOXO3a-BRD4 complex or CDK6 enhances AKTi's antiproliferative and pro-apoptotic effects. These findings highlight phenothiazines’ potential to modulate FOXO factors and support future research into combination therapies with AKTi (31).

2.5. Phenothiazines Modulate Key Signaling Pathways in Cancer Cells

Phenothiazines disrupt critical cancer signaling pathways, including PI3K/Akt/mTOR and MAPK/ERK1/2, to inhibit proliferation, induce apoptosis, and enhance autophagy. Chlorpromazine, for instance, exhibits antitumor activity by modulating p53, Ras, and dopamine receptor D2 (DRD2), which regulate cell cycle progression, metastasis, and chemoresistance. In endometrial cancer, it downregulates IGF-IR and PI3K/Akt phosphorylation via DRD2, while in glioblastoma, it disrupts K-Ras membrane localization, leading to apoptosis and autophagy. Chlorpromazine also induces ER stress and oxidative damage, selectively targeting chemoresistant cells (34, 61, 80, 86).

Thioridazine further modulates pathways like PI3K/Akt/mTOR, suppressing tumor growth by downregulating cyclins and upregulating p21 and p27. It enhances ER stress via the eIF2α/ATF4/CHOP pathway, promoting immunogenic cell death and synergizing with oxaliplatin in colorectal cancer models. In glioblastoma, thioridazine activates AMPK and Wnt/β-catenin signaling, inducing autophagy-associated apoptosis and sensitizing cells to temozolomide by blocking autophagic flux (50, 87-89). These findings highlight phenothiazines’ potential to target diverse pathways and overcome resistance mechanisms in cancer therapy.

2.6. Phenothiazines Inhibit Tumor Angiogenesis

Phenothiazines inhibit angiogenesis—essential for tumor growth—by suppressing VEGF production and interfering with VEGF-mediated signaling, along with other angiogenesis-related pathways like MAPK (26). Trifluoperazine treatment has been shown to reduce microvessel density (MVD) and VEGF levels in vivo, thereby limiting tumor growth (42). Pulkoski-Gross et al. (2015) found that trifluoperazine notably decreased angiogenesis, reduced VEGF expression, and inhibited cancer cell invasion by lowering phosphorylated AKT and β-catenin levels (90). Additionally, thioridazine disrupts pathways downstream of PI3K, including Akt, PDK1, and mTOR, through VEGFR-2, thereby modulating endothelial cell function and inhibiting angiogenesis. This suggests thioridazine’s potential as an anti-angiogenic agent, particularly in ovarian cancer (91).

2.7. Phenothiazines and the AMPK/mTOR/ULK1 Pathway in Cancer Mitophagy

Mitophagy, a selective form of autophagy, removes and recycles damaged mitochondria. In cancer, reduced mitophagy can promote tumor growth by allowing damaged mitochondria to accumulate, increasing oxidative stress and genomic instability (92). Reactive oxygen species (ROS) can activate AMPK, a key regulator of autophagy and energy metabolism, while mTOR negatively regulates autophagy when phosphorylated, and ULK1 initiates autophagy (93). Research has shown that mitophagy regulation involves the AMPK/mTOR/ULK1 pathway (94). Recent studies highlight the role of this pathway in malignancy (95). Shen et al. (2024) found that trifluoperazine exerts anti-osteosarcoma effects by enhancing mitophagy through the AMPK/mTOR/ULK1 pathway. Trifluoperazine reduced P62 and increased LC3B II, ATG5, and Bclin-1 expression, markers of autophagy in osteosarcoma cells (30). It also promoted mitochondrial damage through ROS accumulation, thereby inducing mitophagy and displaying antioxidant effects (30).

2.8. Phenothiazines and Nrf2-Mediated Pathways in Oxidative Stress Modulation

Phenothiazines modulate oxidative stress, a condition characterized by excessive reactive oxygen and nitrogen species (ROS/RNS) that damage proteins, nucleic acids, and lipids, contributing to inflammation, apoptosis, and cancer progression. These compounds activate the Nrf2/ARE pathway, which enhances antioxidant gene expression and suppresses pro-inflammatory mediators like iNOS. In cancer, Nrf2 acts as a double-edged sword, suppressing tumor growth while also promoting drug resistance under stress (96-98). Thioridazine demonstrates Nrf2 activation by increasing ROS production, reducing SIRT1/Nrf2 expression, and inhibiting proliferation in liver cancer cells. It also upregulates proteasome subunit alpha 5 (PSMA5) and, in combination with curcumin, enhances Nrf2 activity via NOX4-dependent ROS, leading to proteasomal degradation of anti-apoptotic proteins like C-FLIP and Mcl-1. These actions highlight phenothiazines' potential in targeting oxidative stress pathways (40, 72). While promising preclinical results suggest therapeutic potential for oxidative stress-linked diseases, including cancer, no phenothiazine derivatives are clinically approved for Nrf2 modulation. Further research is needed to optimize these agents for clinical application.

2.9. Phenothiazines and Cyclooxygenase-2 Inhibitory Activity as a Possible Mechanism for Anticancer Activity

Cyclooxygenase-2 (COX-2) contributes to carcinogenesis and the malignant characteristics of cancer cells through at least six different pathways, including immunological regulation, increased mutagenesis, improved invasion, increased angiogenesis, and suppression of apoptosis (99). Tumor development is often accompanied by inflammation, which is associated with increased expression of COX-2, the inducible form of cyclooxygenase typically absent in healthy tissue (100, 101). Additionally, higher COX-2 levels have been observed in MDR cells compared to chemotherapy-sensitive cancer cells (102, 103).

Although concerns about the potential toxic effects of systemic selective inhibition have raised doubts about the safety of COX-2 inhibition as a chemotherapy prevention technique, selective COX-2 inhibitors were initially considered promising candidate chemotherapy drugs (99). Some phenothiazine derivatives have been reported to possess anti-inflammatory activity, though most reports originate from animal studies and do not discuss the molecular mechanism of their anti-inflammatory action (104, 105). An approach based on computational and combinatorial chemistry methods yielded a phenothiazine-type lead compound that was a selective COX-2 inhibitor (106).

Prior to 2019, the impact of phenothiazine derivatives on COX-2 was poorly understood. However, Sroda-Pomianek et al. (2019) investigated the effects of fluphenazine, MAE-TPR, and APh-FLU, both individually and in combination with simvastatin, on cell growth, apoptosis, and COX-2 activity and expression within the LoVo/Dx cell line (36). Simvastatin and all phenothiazine derivatives, except APh-FLU, reduced the expression of COX-2 protein. The combined treatment of LoVo/Dx cells with phenothiazine derivatives and simvastatin resulted in a further decrease in COX-2 activity. However, the reduction of COX-2 protein expression was similar in both single-agent treatment and the application of the phenothiazine derivatives: Simvastatin mixture (36).

3. Results

3.1. Phenothiazines: Antibacterial Effects and Antibiotic Resistance

Antimicrobial resistance (AMR) poses a critical threat to global health, with the World Health Organization (WHO) identifying it as a "silent pandemic" and one of the top ten global health threats. Antimicrobial resistance is driven by factors such as bacterial evolution, antibiotic overuse, and inadequate public awareness, and it is projected to cause up to 10 million deaths annually by 2050 (107). To address this urgent threat, the WHO has prioritized certain pathogens, including Mycobacterium tuberculosis, which causes 1.8 million deaths each year, and has classified pathogens into critical (e.g., carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa), high (e.g., vancomycin-resistant Enterococcus faecium, MRSA), and medium priority groups (e.g., penicillin-resistant Streptococcus pneumoniae) based on their resistance profiles (108).

The emergence of MDR and extensively drug-resistant (XDR) pathogens has outpaced the efficacy of conventional antibiotics, necessitating innovative approaches to combat AMR (109). MDR bacteria are increasingly resilient due to widespread antibiotic misuse, while MDR cancer cells present parallel challenges in cancer therapy, often leading to relapses (110). Both bacteria and cancer cells share resistance mechanisms, including drug inactivation, EP overexpression, and target modifications (111). In bacteria, EPs facilitate biofilm formation and virulence, while in cancer cells, EPs contribute to drug extrusion and metastasis (112).

3.2. The Antimicrobial Action of Phenothiazines

Phenothiazines, including the FDA-approved chlorpromazine, display antibacterial and EP inhibitory properties against various pathogens, such as Mycobacteria, gram-positive, and gram-negative bacteria like P. aeruginosa. These properties suggest their potential as adjunctive therapies to antibiotics (29). Chlorpromazine also inhibits quorum sensing in Chromobacterium violaceum and Serratia marcescens (113), while miconazole can reduce virulence gene expression in P. aeruginosa (114).

In vitro screening (Table 3) shows that chlorpromazine, promazine, methdilazine, fluphenazine, trimeprazine, trifluoperazine, and flupenthixol exhibit minimum inhibitory concentration (MIC) values around 10 µg/mL against most gram-positive bacteria, with methdilazine and fluphenazine being effective at concentrations as low as 2 - 5 µg/mL for some strains (115). Trifluoperazine was particularly active against gram-positive bacteria, with MICs as low as 2 µg/mL. Among gram-negative bacteria, Vibrio species were most sensitive, while Salmonella and Shigella strains showed varying sensitivities. Klebsiella, pseudomonads, and Acinetobacter species exhibited high resistance to these compounds. Most phenothiazines were bacteriostatic, though some could kill pathogens within 6 to 18 hours (115).

Table 3.

Antibacterial Activity of Synthetic Phenothiazines by In Vitro Screening

Phenothiazine	Antibacterial Activity	MIC µg/mL for Gram Positive Organisms	MIC µg/mL for Gram Negative Organisms	Reference
Chlorpromazine	Bactericidal for gram positive organisms; Bacteriostatic for gram negative organisms	10 - 50	25 - 100	Dastidar et al. (115)
Promazine	Bacteriostatic	10 - 50	10 - 100
Prochlorperazine	Bacteriostatic	25 - 100	50 - 400
Fluphenazine	Bactericidal	10 - 100	10 - 100
Trifluoperazine	Bactericidal	10 - 100	25 - 200
Thioridazine	Bactericidal for gram positive organisms; Bacteriostatic for gram negative organisms	32 - 64 and 50 - 800	100 - 800
Triflupromazine	Bactericidal	2 - 50	2 - 100
Flupenthixol	Bacteriostatic	5 - 50	10 - 100
Promethazine	Bacteriostatic	50 - 200	100 - 200
Methdilazine	Bactericidal	10 - 100	25 - 200
Trimeprazine	Bactericidal	10 - 100	10 - 100

Abbreviation: MIC, minimum inhibitory concentration.

Table 4 summarizes studies investigating the preventative effects of phenothiazines against antibiotic resistance and their associated mechanisms.

Table 4.

Phenothiazines Preventive Effect Against Antibiotic Resistance and the Relevant Mechanisms

Authors, References	Phenothiazine	Infection and Strains	Effect and Mechanism of Action
Kaatz et al. (116)	Chlorpromazine, fluphenazine, thioridazine, prochlorperazine	Staphylococcus aureus (various strains)	Potent inhibitors of NorA EP, especially against strains SA-K1748 and SA-K2068; increases ethidium bromide (EtBr) accumulation
Kristiansen et al. (117)	Chlorpromazine, thioridazine	MRSA, MSSA	Kills S. aureus strains irrespective of oxacillin resistance; likely EP inhibition
Chan et al. (118)	Prochlorperazine, chlorpromazine, promazine	Burkholderia pseudomallei	Enhances efficacy of aminoglycosides and macrolides by inhibiting EPs BpeAB-OprB and AmrAB-OprA, disrupting proton gradient
Bailey et al. (119)	Thioridazine, trifluoperazine, chlorpromazine	Salmonella enterica (Typhimurium)	Increases antibiotic efficacy by inhibiting AcrB EP, enhancing EtBr uptake
Rodrigues et al. (120)	Thioridazine, chlorpromazine	Mycobacterium avium, Mycobacterium smegmatis	Increases erythromycin susceptibility by inhibiting efflux, enhancing EtBr accumulation in a temperature-dependent manner
Dutta et al. (121)	Thioridazine	M. tuberculosis	Alters gene expression related to cell-envelope integrity, EPs, and stress response, inducing cell-envelope damage
Grimsey et al. (122)	Chlorpromazine	Salmonella typhimurium, Escherichia coli	Inhibits AcrB EP by binding within the hydrophobic trap, preventing substrate binding and efflux
McCusker et al. (123)	Thioridazine, chlorpromazine	Enterobacter aerogenes (various isolates)	Inhibits MDR phenotype by reducing ciprofloxacin and chloramphenicol resistance, increasing Hoechst dye accumulation
Nove et al. (124)	Promethazine	E. coli (K-12 AG100)	Induces stress response in acidic pH; upregulates EP genes (acrA, acrB) for toxic substance removal
Sidrim et al. (125)	Promethazine	B. pseudomallei (various isolates)	Disrupts biofilm structure, lowering MICs and MBECs for several antibiotics, improving antibiotic efficacy

Abbreviations: EP, efflux pump; MIC, minimum inhibitory concentration.

3.3. Possible Mechanisms of the Antimicrobial Action of Phenothiazines

Phenothiazines disrupt microbial growth by targeting bacterial membranes, nucleic acids, and EP mechanisms. These compounds inhibit calmodulin-like proteins in bacteria, intercalate into DNA, impair replication processes, and enhance bacterial susceptibility to antibiotics by affecting efflux systems (29, 126).

3.4. Phenothiazines: Targeting Bacterial Membranes and Cell Wall

Phenothiazines, such as chlorpromazine, exhibit both bacteriostatic and bactericidal effects depending on the concentration. They impair potassium transport, alter membrane permeability, and disrupt bacterial haemolysins. Chlorpromazine induces elongation and filamentation in E. coli, alters protein patterns in bacterial envelopes, and affects antibody recognition of the O antigen in Salmonella by binding to a 55 kDa protein (127-130). Thioridazine rapidly destroys gram-positive bacteria and damages the nuclear and cytoplasmic membranes of Trypanosoma brucei while accumulating in macrophages, where it reaches bactericidal levels (131, 132).

3.5. Phenothiazines: Targeting Nucleic Acids and Cellular Replication

Phenothiazines intercalate into DNA, leading to single-stranded breaks and disrupting essential processes like replication and transcription. Their binding affinity depends on guanine-cytosine content, and they may act as plasmid-curing agents by inhibiting plasmid replication at sub-inhibitory levels (133, 134). As calmodulin antagonists, phenothiazines disrupt calcium signaling pathways in prokaryotic and eukaryotic cells, slowing replication and cell cycle progression. For example, chlorpromazine inhibits conformational changes in Schistosoma mansoni calmodulins and reduces nuclear calmodulin activity in Candida albicans, delaying entry into the S and G1 phases (3, 135). Phenothiazines also induce morphological changes at sub-MIC levels. In E. coli, they cause temporary filamentation, while in S. aureus, they inhibit cell division and form mesosome-like structures. In Salmonella typhimurium, chlorpromazine alters the cell wall of resistant mutants by eliminating the 55 kDa protein, unblocking anti-O antibody binding to O antigens and enhancing antimicrobial activity (130).

3.6. Phenothiazines and Bacterial Efflux Pumps: Vital Pathway in Drug Resistance

Bacterial EPs expel toxins, aid stress adaptation, and contribute to virulence and drug resistance. EPs are categorized into six families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), small multidrug resistance (SMR), major facilitator superfamily (MFS), resistance-nodulation-division (RND), and proteobacterial antimicrobial compound efflux (PACE), each playing distinct roles in resistance (136). Inhibiting EPs increases bacterial susceptibility to antibiotics by raising intracellular drug concentrations. Phenothiazines act as EP inhibitors (EPIs), with pH-dependent activity, effectively targeting EPs at neutral or alkaline pH by disrupting the proton motive force (PMF)—a key energy source for efflux (137, 138).

Phenothiazines, including thioridazine, chlorpromazine, and fluphenazine, inhibit efflux systems across various bacterial species. For instance, they block NorA-mediated efflux in S. aureus, enhancing oxacillin susceptibility, and inhibit the proton gradient in B. pseudomallei, disrupting erythromycin efflux (117, 118). In M. smegmatis and M. avium, they increase intracellular ethidium bromide retention, and in M. tuberculosis, chlorpromazine impairs respiration and inhibits the AcrB pump in S. typhimurium (121). Chlorpromazine also reverses chloramphenicol resistance in Enterobacter aerogenes, significantly reducing its MIC (123).

Promethazine demonstrates EPI activity with notable variability across pH levels. In E. coli K12 AG100, its efficacy declines under acidic conditions due to the enhanced efficiency of the AcrAB-TolC pump but upregulates acrA and acrB genes as a bacterial defense mechanism (124). Promethazine also disrupts bacterial biofilms, enhancing antibiotic penetration and efficacy in B. pseudomallei against drugs like erythromycin and ciprofloxacin, offering a potential strategy for combating biofilm-associated resistance (125).

4. Conclusions

Phenothiazines represent a versatile class of compounds with significant potential beyond their psychiatric origins. This review highlights their multifaceted therapeutic applications, particularly in oncology and infectious disease. In cancer, phenothiazines induce apoptosis, disrupt critical signaling pathways, and inhibit angiogenesis. Their activation of the Nrf2/ARE pathway suggests anti-inflammatory and antioxidant potential. In infectious disease, their ability to modulate bacterial EPs underscores their role in combating antibiotic resistance and enhancing antimicrobial efficacy. These findings establish a strong foundation for the continued exploration of phenothiazines as adjunct therapies in cancer and resistant infections. Advancing our understanding of their mechanisms and optimizing their application could unlock innovative treatment options across diverse medical contexts.

4.1. Future Prospects and Recommendations

Originally developed as antipsychotics, phenothiazines have emerged as promising agents in oncology and infectious disease treatment. Their ability to disrupt cancer pathways—such as PDK1/Akt, MAPK/ERK1/2, and Akt/mTOR—alongside their role in apoptosis induction and angiogenesis inhibition, highlights their therapeutic versatility. Furthermore, phenothiazines’ modulation of bacterial EPs offers potential for addressing antibiotic resistance.

Future research should prioritize optimizing phenothiazine derivatives, exploring synergistic effects with existing anticancer and antimicrobial agents, and conducting robust clinical trials to validate their safety and efficacy. Investigations into their interactions with neurotransmitter systems could also reveal novel therapeutic applications. Combining phenothiazines with immunotherapies may enhance anti-tumor responses, while tailored combinations against specific cancers or bacterial pathogens could improve treatment precision.

Comprehensive pharmacokinetic studies are essential to assess long-term effects, drug interactions, and dosing strategies. Additionally, developing phenothiazine derivatives with enhanced selectivity and bioavailability could expand their therapeutic reach and improve clinical outcomes.

Footnotes

Authors' Contribution: X. Z.: Study concept and design; X. Z. and B. X.: Analysis and interpretation of data; X. Z. and B. X.: Drafting of the manuscript; X. Z. and B. X.: Critical revision of the manuscript for important intellectual content.
Conflict of Interests Statement: The authors declared no conflict of interest.
Funding/Support: This research was supported by the Jiangsu Province College Students' Innovation and Entrepreneurship Training Program Project (No. 202311117095Y).

References

1.
Morja MI, Chikhalia KH. Transition metal-free synthesis and functionalization of phenothiazines. Tetrahedron. 2023;145. https://doi.org/10.1016/j.tet.2023.133618.
2.
Jaszczyszyn A, Gasiorowski K, Swiatek P, Malinka W, Cieslik-Boczula K, Petrus J, et al. Chemical structure of phenothiazines and their biological activity. Pharmacol Rep. 2012;64(1):16-23. [PubMed ID: 22580516]. https://doi.org/10.1016/s1734-1140(12)70726-0.
3.
Ford JM, Prozialeck WC, Hait WN. Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. Mol Pharmacol. 1989;35(1):105-15. [PubMed ID: 2563302].
4.
Pajeva IK, Wiese M, Cordes HP, Seydel JK. Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability. J Cancer Res Clin Oncol. 1996;122(1):27-40. [PubMed ID: 8543589]. https://doi.org/10.1007/BF01203070.
5.
Hendrich AB, Wesolowska O, Motohashi N, Molnar J, Michalak K. New phenothiazine-type multidrug resistance modifiers: anti-MDR activity versus membrane perturbing potency. Biochem Biophys Res Commun. 2003;304(2):260-5. [PubMed ID: 12711308]. https://doi.org/10.1016/s0006-291x(03)00580-1.
6.
Morak-Mlodawska B, Jelen M, Pluta K. [New derivatives of phenothiazines with anticancer activities]. Pol Merkur Lekarski. 2009;26(156):671-5. [PubMed ID: 19711740].
7.
Motohashi N, Kawase M, Satoh K, Sakagami H. Cytotoxic potential of phenothiazines. Curr Drug Targets. 2006;7(9):1055-66. [PubMed ID: 17017885]. https://doi.org/10.2174/138945006778226624.
8.
Casey JF, Lasky JJ, Klett CJ, Hollister LE. Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital. Am J Psychiatry. 1960;117:97-105. [PubMed ID: 13808146]. https://doi.org/10.1176/ajp.117.2.97.
9.
Winkelman NJ. Chlorpromazine in the treatment of neuropsychiatric disorders. J Am Med Assoc. 1954;155(1):18-21. [PubMed ID: 13151880]. https://doi.org/10.1001/jama.1954.03690190024007.
10.
Bhargava KP, Chandra O. Anti-Emetic Activity of Phenothiazines in Relation to Their Chemical Structure. Br J Pharmacol Chemother. 1963;21(3):436-40. [PubMed ID: 14110743]. [PubMed Central ID: PMC1703878]. https://doi.org/10.1111/j.1476-5381.1963.tb02011.x.
11.
Kidron A, Nguyen H. Phenothiazine. Florida, United States: StatPearls; 2023.
12.
Peroutka SJ, Synder SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry. 1980;137(12):1518-22. [PubMed ID: 6108081]. https://doi.org/10.1176/ajp.137.12.1518.
13.
Mozrzymas JW, Barberis A, Michalak K, Cherubini E. Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors. J Neurosci. 1999;19(7):2474-88. [PubMed ID: 10087062]. [PubMed Central ID: PMC6786064]. https://doi.org/10.1523/JNEUROSCI.19-07-02474.1999.
14.
Teisseyre A, Michalak K. The voltage- and time-dependent blocking effect of trifluoperazine on T lymphocyte Kv1.3 channels. Biochem Pharmacol. 2003;65(4):551-61. [PubMed ID: 12566082]. https://doi.org/10.1016/s0006-2952(02)01561-7.
15.
JO COLE, DJ CLYDE. Extrapyramidal side effects and clinical response to the phenothiazines. Rev Can Biol. 1961;20:565-74.
16.
Wilson WH, Weiler SJ. Case report of phenothiazine-induced torsade de pointes. Am J Psychiatry. 1984;141(10):1265-6. [PubMed ID: 6148894]. https://doi.org/10.1176/ajp.141.10.1265.
17.
Biel JH, Bopp BA. Amphetamines: Structure-Activity Relationships. Stimulants. 1978. p. 1-39. https://doi.org/10.1007/978-1-4757-0510-2_1.
18.
Trombik P, Cieslik-Boczula K. Influence of phenothiazine molecules on the interactions between positively charged poly-l-lysine and negatively charged DPPC/DPPG membranes. Spectrochim Acta A Mol Biomol Spectrosc. 2020;227:117563. [PubMed ID: 31689607]. https://doi.org/10.1016/j.saa.2019.117563.
19.
Yu Q, Cai Q, Liang W, Zhong K, Liu J, Li H, et al. Design of phenothiazine-based cationic amphiphilic derivatives incorporating arginine residues: Potential membrane-active broad-spectrum antimicrobials combating pathogenic bacteria in vitro and in vivo. Eur J Med Chem. 2023;260:115733. [PubMed ID: 37643545]. https://doi.org/10.1016/j.ejmech.2023.115733.
20.
Rodrigues T. Chemical and photochemical behavior of phenothiazines in heterogeneous media related to a diversity of biological effects. Catalysis and photochemistry in heterogeneous media. Kerala: Research Signpost. 2007:75-90.
21.
Hostetler KY, Matsuzawa Y. Studies on the mechanism of drug-induced lipidosis. Cationic amphiphilic drug inhibition of lysosomal phospholipases A and C. Biochem Pharmacol. 1981;30(10):1121-6. [PubMed ID: 7259794]. https://doi.org/10.1016/0006-2952(81)90451-2.
22.
Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci. 2007;96(4):729-46. [PubMed ID: 17117426]. https://doi.org/10.1002/jps.20792.
23.
Ellegaard AM, Dehlendorff C, Vind AC, Anand A, Cederkvist L, Petersen NHT, et al. Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment. EBioMedicine. 2016;9:130-9. [PubMed ID: 27333030]. [PubMed Central ID: PMC4972561]. https://doi.org/10.1016/j.ebiom.2016.06.013.
24.
Daniel JA, Chau N, Abdel-Hamid MK, Hu L, von Kleist L, Whiting A, et al. Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis. Traffic. 2015;16(6):635-54. [PubMed ID: 25693808]. https://doi.org/10.1111/tra.12272.
25.
Chew HY, De Lima PO, Gonzalez Cruz JL, Banushi B, Echejoh G, Hu L, et al. Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies. Cell. 2020;180(5):895-914 e27. [PubMed ID: 32142680]. https://doi.org/10.1016/j.cell.2020.02.019.
26.
Varga B, Csonka Á, Csonka A, Molnar J, Amaral L, Spengler G. Possible Biological and Clinical Applications of Phenothiazines. Anticancer Research. 2017;37(11). https://doi.org/10.21873/anticanres.12045.
27.
Dinic J, Efferth T, Garcia-Sosa AT, Grahovac J, Padron JM, Pajeva I, et al. Repurposing old drugs to fight multidrug resistant cancers. Drug Resist Updat. 2020;52:100713. [PubMed ID: 32615525]. https://doi.org/10.1016/j.drup.2020.100713.
28.
Wang Y, Xia L, Lin J, Gong L, Xia Y, Xu Y, et al. Thioridazine combined with carboplatin results in synergistic inhibition of triple negative breast cancer by targeting cancer stem cells. Transl Oncol. 2022;26:101549. [PubMed ID: 36191461]. [PubMed Central ID: PMC9530598]. https://doi.org/10.1016/j.tranon.2022.101549.
29.
Grimsey EM, Piddock LJV. Do phenothiazines possess antimicrobial and efflux inhibitory properties? FEMS Microbiol Rev. 2019;43(6):577-90. [PubMed ID: 31216574]. https://doi.org/10.1093/femsre/fuz017.
30.
Shen W, Zeng X, Zeng X, Hu B, Ren C, Lin Z, et al. Trifluoperazine activates AMPK / mTOR / ULK1 signaling pathway to induce mitophagy in osteosarcoma cells. Chem Biol Interact. 2024;392:110904. [PubMed ID: 38360085]. https://doi.org/10.1016/j.cbi.2024.110904.
31.
Liu J, Duan Z, Guo W, Zeng L, Wu Y, Chen Y, et al. Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. Nat Commun. 2018;9(1):5200. [PubMed ID: 30518851]. [PubMed Central ID: PMC6281582]. https://doi.org/10.1038/s41467-018-07258-y.
32.
Oliva CR, Zhang W, Langford C, Suto MJ, Griguer CE. Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget. 2017;8(23):37568-83. [PubMed ID: 28455961]. [PubMed Central ID: PMC5514931]. https://doi.org/10.18632/oncotarget.17247.
33.
Cui Y, Wu H, Yang L, Huang T, Li J, Gong X, et al. Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB. Front Oncol. 2021;11:665832. [PubMed ID: 33937078]. [PubMed Central ID: PMC8087176]. https://doi.org/10.3389/fonc.2021.665832.
34.
Matteoni S, Matarrese P, Ascione B, Ricci-Vitiani L, Pallini R, Villani V, et al. Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response. J Exp Clin Cancer Res. 2021;40(1):347. [PubMed ID: 34740374]. [PubMed Central ID: PMC8569984]. https://doi.org/10.1186/s13046-021-02144-w.
35.
Xi H, Wu M, Ma H, Li S, Huang Q, Zhang Y, et al. Repurposing fluphenazine to suppress melanoma brain, lung and bone metastasis by inducing G0/G1 cell cycle arrest and apoptosis and disrupting autophagic flux. Clin Exp Metastasis. 2023;40(2):161-75. [PubMed ID: 36952079]. https://doi.org/10.1007/s10585-023-10202-0.
36.
Sroda-Pomianek K, Michalak K, Palko-Labuz A, Uryga A, Swiatek P, Majkowski M, et al. The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells. Int J Mol Sci. 2019;20(4). [PubMed ID: 30813251]. [PubMed Central ID: PMC6412564]. https://doi.org/10.3390/ijms20040955.
37.
Qian G, Dai L, Yu T. Thioridazine Sensitizes Cisplatin Against Chemoresistant Human Lung and Ovary Cancer Cells. DNA Cell Biol. 2019;38(7):718-24. [PubMed ID: 31188023]. https://doi.org/10.1089/dna.2019.4715.
38.
Medeiros HCD, Colturato-Kido C, Ferraz LS, Costa CA, Moraes VWR, Paredes-Gamero EJ, et al. AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia. Chem Biol Interact. 2020;315:108888. [PubMed ID: 31682805]. https://doi.org/10.1016/j.cbi.2019.108888.
39.
Tan X, Gong L, Li X, Zhang X, Sun J, Luo X, et al. Promethazine inhibits proliferation and promotes apoptosis in colorectal cancer cells by suppressing the PI3K/AKT pathway. Biomed Pharmacother. 2021;143:112174. [PubMed ID: 34560542]. https://doi.org/10.1016/j.biopha.2021.112174.
40.
El-Sayed Ibrahim N, Morsy H, Abdelgwad M. The Comparative Effect of Nisin and Thioridazine as Potential Anticancer Agents on Hepatocellular Carcinoma. Rep Biochem Mol Biol. 2021;9(4):452-62. [PubMed ID: 33969139]. [PubMed Central ID: PMC8068446]. https://doi.org/10.52547/rbmb.9.4.452.
41.
Jhou AJ, Chang HC, Hung CC, Lin HC, Lee YC, Liu WT, et al. Chlorpromazine, an antipsychotic agent, induces G2/M phase arrest and apoptosis via regulation of the PI3K/AKT/mTOR-mediated autophagy pathways in human oral cancer. Biochem Pharmacol. 2021;184:114403. [PubMed ID: 33388284]. https://doi.org/10.1016/j.bcp.2020.114403.
42.
Jiang J, Huang Z, Chen X, Luo R, Cai H, Wang H, et al. Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma. DNA Cell Biol. 2017;36(10):813-21. [PubMed ID: 28876084]. https://doi.org/10.1089/dna.2017.3790.
43.
Zhelev Z, Ohba H, Bakalova R, Hadjimitova V, Ishikawa M, Shinohara Y, et al. Phenothiazines suppress proliferation and induce apoptosis in cultured leukemic cells without any influence on the viability of normal lymphocytes. Phenothiazines and leukemia. Cancer Chemother Pharmacol. 2004;53(3):267-75. [PubMed ID: 14663628]. https://doi.org/10.1007/s00280-003-0738-1.
44.
Eisenberg S, Giehl K, Henis YI, Ehrlich M. Differential interference of chlorpromazine with the membrane interactions of oncogenic K-Ras and its effects on cell growth. J Biol Chem. 2008;283(40):27279-88. [PubMed ID: 18693247]. https://doi.org/10.1074/jbc.M804589200.
45.
Klutzny S, Lesche R, Keck M, Kaulfuss S, Schlicker A, Christian S, et al. Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia-specific tumor cell death. Cell Death Dis. 2017;8(3). e2709. [PubMed ID: 28358364]. [PubMed Central ID: PMC5386533]. https://doi.org/10.1038/cddis.2017.130.
46.
Xu F, Xia Y, Feng Z, Lin W, Xue Q, Jiang J, et al. Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases. Am J Cancer Res. 2019;9(3):459.
47.
Heitmann ASB, Zanjani AAH, Klenow MB, Mularski A, Sonder SL, Lund FW, et al. Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair. J Biol Chem. 2021;297(2):101012. [PubMed ID: 34324830]. [PubMed Central ID: PMC8363839]. https://doi.org/10.1016/j.jbc.2021.101012.
48.
Sad K, Parashar P, Tripathi P, Hungyo H, Sistla R, Soni R, et al. Prochlorperazine enhances radiosensitivity of non-small cell lung carcinoma by stabilizing GDP-bound mutant KRAS conformation. Free Radic Biol Med. 2021;177:299-312. [PubMed ID: 34742922]. https://doi.org/10.1016/j.freeradbiomed.2021.11.001.
49.
Jahchan NS, Dudley JT, Mazur PK, Flores N, Yang D, Palmerton A, et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. 2013;3(12):1364-77. [PubMed ID: 24078773]. [PubMed Central ID: PMC3864571]. https://doi.org/10.1158/2159-8290.CD-13-0183.
50.
Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ, et al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012;17(9):989-97. [PubMed ID: 22460505]. [PubMed Central ID: PMC3413814]. https://doi.org/10.1007/s10495-012-0717-2.
51.
Park MS, Dong SM, Kim BR, Seo SH, Kang S, Lee EJ, et al. Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts. Oncotarget. 2014;5(13):4929-34. [PubMed ID: 24952635]. [PubMed Central ID: PMC4148111]. https://doi.org/10.18632/oncotarget.2063.
52.
Song Y, Li L, Chen J, Chen H, Cui B, Feng Y, et al. Thioridazine hydrochloride: an antipsychotic agent that inhibits tumor growth and lung metastasis in triple-negative breast cancer via inducing G0/G1 arrest and apoptosis. Cell Cycle. 2020;19(24):3521-33. [PubMed ID: 33315498]. [PubMed Central ID: PMC7781661]. https://doi.org/10.1080/15384101.2020.1850969.
53.
Cheng HW, Liang YH, Kuo YL, Chuu CP, Lin CY, Lee MH, et al. Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data. Cell Death Dis. 2015;6(5). e1753. [PubMed ID: 25950483]. [PubMed Central ID: PMC4669717]. https://doi.org/10.1038/cddis.2015.77.
54.
Gil-Ad I, Shtaif B, Levkovitz Y, Nordenberg J, Taler M, Korov I, et al. Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. Oncol Rep. 2006;15(1):107-12. [PubMed ID: 16328041].
55.
Zhang X, Ding K, Ji J, Parajuli H, Aasen SN, Espedal H, et al. Trifluoperazine prolongs the survival of experimental brain metastases by STAT3-dependent lysosomal membrane permeabilization. Am J Cancer Res. 2020;10(2):545.
56.
Feng Z, Xia Y, Gao T, Xu F, Lei Q, Peng C, et al. The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis. Cell Death Dis. 2018;9(10):1006. [PubMed ID: 30258182]. [PubMed Central ID: PMC6158270]. https://doi.org/10.1038/s41419-018-1046-3.
57.
Zhang X, Xu R, Zhang C, Xu Y, Han M, Huang B, et al. Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination. J Exp Clin Cancer Res. 2017;36(1):118. [PubMed ID: 28870216]. [PubMed Central ID: PMC5584019]. https://doi.org/10.1186/s13046-017-0588-z.
58.
Choi JH, Yang YR, Lee SK, Kim SH, Kim YH, Cha JY, et al. Potential inhibition of PDK1/Akt signaling by phenothiazines suppresses cancer cell proliferation and survival. Ann N Y Acad Sci. 2008;1138:393-403. [PubMed ID: 18837915]. https://doi.org/10.1196/annals.1414.041.
59.
Kang S, Hong J, Lee JM, Moon HE, Jeon B, Choi J, et al. Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R. Mol Cancer Ther. 2017;16(1):217-27. [PubMed ID: 28062709]. https://doi.org/10.1158/1535-7163.MCT-16-0169-T.
60.
Gangopadhyay S, Karmakar P, Dasgupta U, Chakraborty A. Trifluoperazine stimulates ionizing radiation induced cell killing through inhibition of DNA repair. Mutat Res. 2007;633(2):117-25. [PubMed ID: 17627868]. https://doi.org/10.1016/j.mrgentox.2007.05.011.
61.
Colturato-Kido C, Lopes RM, Medeiros HCD, Costa CA, Prado-Souza LFL, Ferraz LS, et al. Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells. Life (Basel). 2021;11(4). [PubMed ID: 33923896]. [PubMed Central ID: PMC8073363]. https://doi.org/10.3390/life11040365.
62.
Li H, Juan L, Xia L, Wang Y, Bao Y, Sun G. Thioridazine Sensitizes Esophageal Carcinoma Cell Lines to Radiotherapy-Induced Apoptosis In Vitro and In Vivo. Med Sci Monit. 2016;22:2624-34. [PubMed ID: 27453171]. [PubMed Central ID: PMC4970441]. https://doi.org/10.12659/msm.899950.
63.
Shen J, Ma B, Zhang X, Sun X, Han J, Wang Y, et al. Thioridazine has potent antitumor effects on lung cancer stem-like cells. Oncol Lett. 2017;13(3):1563-8. [PubMed ID: 28454291]. [PubMed Central ID: PMC5403693]. https://doi.org/10.3892/ol.2017.5651.
64.
Min KJ, Seo BR, Bae YC, Yoo YH, Kwon TK. Antipsychotic agent thioridazine sensitizes renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated inhibition of Akt signaling and downregulation of Mcl-1 and c-FLIP(L). Cell Death Dis. 2014;5(2). e1063. [PubMed ID: 24556678]. [PubMed Central ID: PMC3944252]. https://doi.org/10.1038/cddis.2014.35.
65.
Seervi M, Rani A, Sharma AK, Santhosh Kumar TR. ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine. Biomed Pharmacother. 2018;106:200-9. [PubMed ID: 29960166]. https://doi.org/10.1016/j.biopha.2018.06.123.
66.
Zhang C, Gong P, Liu P, Zhou N, Zhou Y, Wang Y. Thioridazine elicits potent antitumor effects in colorectal cancer stem cells. Oncol Rep. 2017;37(2):1168-74. [PubMed ID: 28000884]. https://doi.org/10.3892/or.2016.5313.
67.
Mu J, Xu H, Yang Y, Huang W, Xiao J, Li M, et al. Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer. Oncol Rep. 2014;31(5):2107-14. [PubMed ID: 24604290]. https://doi.org/10.3892/or.2014.3068.
68.
Chen IS, Liang WZ, Wang JL, Kuo CC, Hao LJ, Chou CT, et al. Exploration of thioridazine-induced Ca(2+) signaling and non-Ca(2+)-triggered cell death in HepG2 human hepatocellular carcinoma cells. Chin J Physiol. 2020;63(4):187-94. [PubMed ID: 32859886]. https://doi.org/10.4103/CJP.CJP_45_20.
69.
Moraes VWR, Santos VM, Suarez ER, Ferraz LS, Lopes RM, Mognol GP, et al. Targeting Ca(2+) and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells. Life (Basel). 2022;12(10). [PubMed ID: 36294912]. [PubMed Central ID: PMC9605445]. https://doi.org/10.3390/life12101477.
70.
Shin SY, Lee KS, Choi YK, Lim HJ, Lee HG, Lim Y, et al. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis. 2013;34(9):2080-9. [PubMed ID: 23689352]. https://doi.org/10.1093/carcin/bgt169.
71.
Goyette MA, Cusseddu R, Elkholi I, Abu-Thuraia A, El-Hachem N, Haibe-Kains B, et al. AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer. Oncotarget. 2019;10(21):2055-67. [PubMed ID: 31007848]. [PubMed Central ID: PMC6459349]. https://doi.org/10.18632/oncotarget.26725.
72.
Seo SU, Kim TH, Kim DE, Min KJ, Kwon TK. NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biol. 2017;13:608-22. [PubMed ID: 28806703]. [PubMed Central ID: PMC5554966]. https://doi.org/10.1016/j.redox.2017.07.017.
73.
Seo SU, Cho HK, Min KJ, Woo SM, Kim S, Park JW, et al. Thioridazine enhances sensitivity to carboplatin in human head and neck cancer cells through downregulation of c-FLIP and Mcl-1 expression. Cell Death Dis. 2017;8(2). e2599. [PubMed ID: 28182008]. [PubMed Central ID: PMC5386499]. https://doi.org/10.1038/cddis.2017.8.
74.
Nagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, et al. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell. 2012;22(6):825-37. [PubMed ID: 23238017]. https://doi.org/10.1016/j.ccr.2012.11.002.
75.
Lu M, Li J, Luo Z, Zhang S, Xue S, Wang K, et al. Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis. Onco Targets Ther. 2015;8:1543-52. [PubMed ID: 26124671]. [PubMed Central ID: PMC4482370]. https://doi.org/10.2147/OTT.S77373.
76.
Spengler G, Molnar J, Viveiros M, Amaral L. Thioridazine induces apoptosis of multidrug-resistant mouse lymphoma cells transfected with the human ABCB1 and inhibits the expression of P-glycoprotein. Anticancer Res. 2011;31(12):4201-5.
77.
Antherieu S, Bachour-El Azzi P, Dumont J, Abdel-Razzak Z, Guguen-Guillouzo C, Fromenty B, et al. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells. Hepatology. 2013;57(4):1518-29. [PubMed ID: 23175273]. https://doi.org/10.1002/hep.26160.
78.
Yue H, Huang D, Qin L, Zheng Z, Hua L, Wang G, et al. Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine. Biomed Res Int. 2016;2016:6709828. [PubMed ID: 27556038]. [PubMed Central ID: PMC4983333]. https://doi.org/10.1155/2016/6709828.
79.
Dos Santos AF, Terra LF, Wailemann RA, Oliveira TC, Gomes VM, Mineiro MF, et al. Methylene blue photodynamic therapy induces selective and massive cell death in human breast cancer cells. BMC Cancer. 2017;17(1):194. [PubMed ID: 28298203]. [PubMed Central ID: PMC5353937]. https://doi.org/10.1186/s12885-017-3179-7.
80.
Harris S, Nagarajan P, Kim K. The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells. Med Oncol. 2024;41(4):87. [PubMed ID: 38472423]. https://doi.org/10.1007/s12032-024-02323-7.
81.
Xia Y, Xu F, Xiong M, Yang H, Lin W, Xie Y, et al. Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux. Pharmacol Res. 2021;163:105295. [PubMed ID: 33176207]. https://doi.org/10.1016/j.phrs.2020.105295.
82.
Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19(19):5320-8. [PubMed ID: 24089445]. https://doi.org/10.1158/1078-0432.CCR-13-0259.
83.
Jelen M, Otto-Slusarczyk D, Morak-Mlodawska B, Struga M. Novel Tetracyclic Azaphenothiazines with the Quinoline Ring as New Anticancer and Antibacterial Derivatives of Chlorpromazine. Int J Mol Sci. 2024;25(8). [PubMed ID: 38673734]. [PubMed Central ID: PMC11050599]. https://doi.org/10.3390/ijms25084148.
84.
Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol. 2024;25(1):46-64. [PubMed ID: 37710009]. https://doi.org/10.1038/s41580-023-00649-0.
85.
Sangodkar J, Dhawan NS, Melville H, Singh VJ, Yuan E, Rana H, et al. Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response. J Clin Invest. 2012;122(7):2637-51. [PubMed ID: 22653055]. [PubMed Central ID: PMC3386822]. https://doi.org/10.1172/JCI62058.
86.
Chu CS, Lin YS, Liang WZ. The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca(2+) Signaling Pathway in Glial Cell Models. Neurotox Res. 2022;40(3):791-802. [PubMed ID: 35438391]. https://doi.org/10.1007/s12640-022-00507-5.
87.
Saleh AK, El-Mahdy NA, El-Masry TA, El-Kadem AH. Trifluoperazine mitigates cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in mice by modulating the AKT/mTOR-driven autophagy and Nrf2/HO-1 signaling cascades. Life Sci. 2024;344:122566. [PubMed ID: 38499285]. https://doi.org/10.1016/j.lfs.2024.122566.
88.
Tran TH, Kao M, Liu HS, Hong YR, Su Y, Huang CF. Repurposing thioridazine for inducing immunogenic cell death in colorectal cancer via eIF2alpha/ATF4/CHOP and secretory autophagy pathways. Cell Commun Signal. 2023;21(1):184. [PubMed ID: 37488534]. [PubMed Central ID: PMC10364410]. https://doi.org/10.1186/s12964-023-01190-5.
89.
Johannessen TC, Hasan-Olive MM, Zhu H, Denisova O, Grudic A, Latif MA, et al. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. Int J Cancer. 2019;144(7):1735-45. [PubMed ID: 30289977]. https://doi.org/10.1002/ijc.31912.
90.
Pulkoski-Gross A, Li J, Zheng C, Li Y, Ouyang N, Rigas B, et al. Repurposing the antipsychotic trifluoperazine as an antimetastasis agent. Mol Pharmacol. 2015;87(3):501-12. [PubMed ID: 25552486]. [PubMed Central ID: PMC4419284]. https://doi.org/10.1124/mol.114.096941.
91.
Mehrabi SF, Elmi S, Nylandsted J. Repurposing phenothiazines for cancer therapy: compromising membrane integrity in cancer cells. Front Oncol. 2023;13:1320621. [PubMed ID: 38074670]. [PubMed Central ID: PMC10701681]. https://doi.org/10.3389/fonc.2023.1320621.
92.
Picca A, Faitg J, Auwerx J, Ferrucci L, D'Amico D. Mitophagy in human health, ageing and disease. Nat Metab. 2023;5(12):2047-61. [PubMed ID: 38036770]. https://doi.org/10.1038/s42255-023-00930-8.
93.
Lin M, Hua R, Ma J, Zhou Y, Li P, Xu X, et al. Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway. Environ Int. 2021;147:106298. [PubMed ID: 33387880]. https://doi.org/10.1016/j.envint.2020.106298.
94.
Hung CM, Lombardo PS, Malik N, Brun SN, Hellberg K, Van Nostrand JL, et al. AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy. Sci Adv. 2021;7(15). [PubMed ID: 33827825]. [PubMed Central ID: PMC8026119]. https://doi.org/10.1126/sciadv.abg4544.
95.
Shen J, Dong J, Shao F, Zhao J, Gong L, Wang H, et al. Graphene oxide induces autophagy and apoptosis via the ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells. Nanomedicine (Lond). 2022;17(9):591-605. [PubMed ID: 35394351]. https://doi.org/10.2217/nnm-2022-0030.
96.
Wang YT, Chen GC. Regulation of oxidative stress-induced autophagy by ATG9A ubiquitination. Autophagy. 2022;18(8):2008-10. [PubMed ID: 35380918]. [PubMed Central ID: PMC9450972]. https://doi.org/10.1080/15548627.2022.2061756.
97.
Yao Z, Bai Q, Wang G. Mechanisms of Oxidative Stress and Therapeutic Targets following Intracerebral Hemorrhage. Oxid Med Cell Longev. 2021;2021:8815441. [PubMed ID: 33688394]. [PubMed Central ID: PMC7920740]. https://doi.org/10.1155/2021/8815441.
98.
Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M, Karakousi TR, et al. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1. Cell. 2019;178(2):316-329 e18. [PubMed ID: 31257023]. [PubMed Central ID: PMC6625921]. https://doi.org/10.1016/j.cell.2019.06.003.
99.
Mahboubi-Rabbani M, Abdolghaffari AH, Ghesmati M, Amini A, Zarghi A. Selective COX-2 inhibitors as anticancer agents: a patent review (2018-2023). Expert Opin Ther Pat. 2024;34(9):733-57. [PubMed ID: 38958471]. https://doi.org/10.1080/13543776.2024.2373771.
100.
Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Asai K, et al. Expression of cyclooxygenase-1 and-2 in human colorectal cancer. Cancer Res. 1995;55(17):3785-9.
101.
Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA. Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res. 2002;62(6):1676-81.
102.
Qiu ZQ, Qiu ZR. Sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 expression. Asian Pac J Cancer Prev. 2015;16(8):3447-50. [PubMed ID: 25921160]. https://doi.org/10.7314/apjcp.2015.16.8.3447.
103.
Surowiak P, Pawełczyk K, Maciejczyk A, Pudełko M, Kołodziej J, Zabel M, et al. Positive correlation between cyclooxygenase 2 and the expression of ABC transporters in non-small cell lung cancer. Anticancer Res. 2008;28(5B):2967-74.
104.
Kubota K, Kurebayashi H, Miyachi H, Tobe M, Onishi M, Isobe Y. Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H(1) antagonists. Bioorg Med Chem Lett. 2009;19(10):2766-71. [PubMed ID: 19362477]. https://doi.org/10.1016/j.bmcl.2009.03.124.
105.
Sharma S, Srivastava VK, Kumar A. Synthesis and anti-inflammatory activity of some heterocyclic derivatives of phenothiazine. Die Pharmazie-An Int J Pharmaceutical Sci. 2005;60(1):18-22.
106.
Stewart KD, Loren S, Frey L, Otis E, Klinghofer V, Hulkower KI. Discovery of a new cyclooxygenase-2 lead compound through 3-D database searching and combinatorial chemistry. Bioorg Med Chem Lett. 1998;8(5):529-34. [PubMed ID: 9871612]. https://doi.org/10.1016/s0960-894x(98)00068-7.
107.
Antimicrobial Resistance C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-55. [PubMed ID: 35065702]. [PubMed Central ID: PMC8841637]. https://doi.org/10.1016/S0140-6736(21)02724-0.
108.
World Health Organization. 2021 antibacterial agents in clinical and preclinical development: an overview and analysis. 2022. Available from: https://www.who.int/publications/i/item/9789240047655.
109.
Breijyeh Z, Karaman R. Design and Synthesis of Novel Antimicrobial Agents. Antibiotics (Basel). 2023;12(3). [PubMed ID: 36978495]. [PubMed Central ID: PMC10045396]. https://doi.org/10.3390/antibiotics12030628.
110.
Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis. 2018;35(4):309-18. [PubMed ID: 29799080]. https://doi.org/10.1007/s10585-018-9903-0.
111.
Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol. 2018;4(3):482-501. [PubMed ID: 31294229]. [PubMed Central ID: PMC6604941]. https://doi.org/10.3934/microbiol.2018.3.482.
112.
Alav I, Sutton JM, Rahman KM. Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother. 2018;73(8):2003-20. [PubMed ID: 29506149]. https://doi.org/10.1093/jac/dky042.
113.
Gajdacs M, Spengler G. The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors. Antibiotics (Basel). 2019;8(4). [PubMed ID: 31861228]. [PubMed Central ID: PMC6963710]. https://doi.org/10.3390/antibiotics8040270.
114.
D'Angelo F, Baldelli V, Halliday N, Pantalone P, Polticelli F, Fiscarelli E, et al. Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62(11). [PubMed ID: 30201815]. [PubMed Central ID: PMC6201120]. https://doi.org/10.1128/AAC.01296-18.
115.
Dastidar SG, Kristiansen JE, Molnar J, Amaral L. Role of Phenothiazines and Structurally Similar Compounds of Plant Origin in the Fight against Infections by Drug Resistant Bacteria. Antibiotics (Basel). 2013;2(1):58-72. [PubMed ID: 27029292]. [PubMed Central ID: PMC4790298]. https://doi.org/10.3390/antibiotics2010058.
116.
Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE. Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47(2):719-26. [PubMed ID: 12543683]. [PubMed Central ID: PMC151737]. https://doi.org/10.1128/AAC.47.2.719-726.2003.
117.
Kristiansen MM, Leandro C, Ordway D, Martins M, Viveiros M, Pacheco T, et al. Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro. Int J Antimicrob Agents. 2003;22(3):250-3. [PubMed ID: 13678829]. https://doi.org/10.1016/s0924-8579(03)00200-0.
118.
Chan YY, Ong YM, Chua KL. Synergistic interaction between phenothiazines and antimicrobial agents against Burkholderia pseudomallei. Antimicrob Agents Chemother. 2007;51(2):623-30. [PubMed ID: 17145801]. [PubMed Central ID: PMC1797753]. https://doi.org/10.1128/AAC.01033-06.
119.
Bailey AM, Paulsen IT, Piddock LJ. RamA confers multidrug resistance in Salmonella enterica via increased expression of acrB, which is inhibited by chlorpromazine. Antimicrob Agents Chemother. 2008;52(10):3604-11. [PubMed ID: 18694955]. [PubMed Central ID: PMC2565896]. https://doi.org/10.1128/AAC.00661-08.
120.
Rodrigues L, Wagner D, Viveiros M, Sampaio D, Couto I, Vavra M, et al. Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother. 2008;61(5):1076-82. [PubMed ID: 18310137]. https://doi.org/10.1093/jac/dkn070.
121.
Dutta NK, Mehra S, Kaushal D. A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine. PLoS One. 2010;5(4). e10069. [PubMed ID: 20386700]. [PubMed Central ID: PMC2851646]. https://doi.org/10.1371/journal.pone.0010069.
122.
Grimsey EM, Fais C, Marshall RL, Ricci V, Ciusa ML, Stone JW, et al. Chlorpromazine and Amitriptyline Are Substrates and Inhibitors of the AcrB Multidrug Efflux Pump. mBio. 2020;11(3). [PubMed ID: 32487753]. [PubMed Central ID: PMC7267879]. https://doi.org/10.1128/mBio.00465-20.
123.
McCusker MP, Alves Ferreira D, Cooney D, Martins Alves B, Fanning S, Pages JM, et al. Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers. J Glob Antimicrob Resist. 2019;16:187-98. [PubMed ID: 30321623]. https://doi.org/10.1016/j.jgar.2018.10.009.
124.
Nove M, Kincses A, Molnar J, Amaral L, Spengler G. The Role of Efflux Pumps and Environmental pH in Bacterial Multidrug Resistance. In Vivo. 2020;34(1):65-71. [PubMed ID: 31882464]. [PubMed Central ID: PMC6984089]. https://doi.org/10.21873/invivo.11746.
125.
Sidrim JJ, Vasconcelos DC, Riello GB, Guedes GM, Serpa R, Bandeira TJ, et al. Promethazine improves antibiotic efficacy and disrupts biofilms of Burkholderia pseudomallei. Biofouling. 2017;33(1):88-97. [PubMed ID: 27936915]. https://doi.org/10.1080/08927014.2016.1262846.
126.
Adkin P, Hitchcock A, Smith LJ, Walsh SE. Priming with biocides: A pathway to antibiotic resistance? J Appl Microbiol. 2022;133(2):830-41. [PubMed ID: 35384175]. [PubMed Central ID: PMC9543593]. https://doi.org/10.1111/jam.15564.
127.
Kristiansen JE. Experiments to illustrate the effect of chlorpromazine on the permeability of the bacterial cell wall. Acta Pathol Microbiol Scand B. 1979;87(5):317-9. [PubMed ID: 525356]. https://doi.org/10.1111/j.1699-0463.1979.tb02445.x.
128.
Galeazzi L, Turchetti G, Grilli G, Groppa G, Giunta S. Chlorpromazine as permeabilizer and reagent for detection of microbial peroxidase and peroxidaselike activities. Appl Environ Microbiol. 1986;52(6):1433-5. [PubMed ID: 3539020]. [PubMed Central ID: PMC239250]. https://doi.org/10.1128/aem.52.6.1433-1435.1986.
129.
Amaral L, Lorian V. Effects of chlorpromazine on the cell envelope proteins of Escherichia coli. Antimicrob Agents Chemother. 1991;35(9):1923-4. [PubMed ID: 1952868]. [PubMed Central ID: PMC245294]. https://doi.org/10.1128/AAC.35.9.1923.
130.
Amaral L, Kristiansen JE, Frolund Thomsen V, Markovich B. The effects of chlorpromazine on the outer cell wall of Salmonella typhimurium in ensuring resistance to the drug. Int J Antimicrob Agents. 2000;14(3):225-9. [PubMed ID: 10773492]. https://doi.org/10.1016/s0924-8579(00)00136-9.
131.
Radhakrishnan V, Ganguly K, Ganguly M, Dastidar SG, Chakrabarty AN. Potentiality of tricyclic compound thioridazine as an effective antibacterial and antiplasmid agent. Indian J Exp Biol. 1999;37(7):671-5.
132.
Page AM, Lagnado JR. Effects of phenothiazine neuroleptic drugs on the microtubular-membrane complex in bloodstream forms of Trypanosoma brucei. Parasitolog. 1995;111 ( Pt 4):493-504. [PubMed ID: 11023414]. https://doi.org/10.1017/s0031182000066002.
133.
Mohiuddin SG, Nguyen TV, Orman MA. Pleiotropic actions of phenothiazine drugs are detrimental to Gram-negative bacterial persister cells. Commun Biol. 2022;5(1):217. [PubMed ID: 35264714]. [PubMed Central ID: PMC8907348]. https://doi.org/10.1038/s42003-022-03172-8.
134.
Sharma S, Kaur H, Khuller GK. Cell cycle effects of the phenothiazines: trifluoperazine and chlorpromazine in Candida albicans. FEMS Microbiol Lett. 2001;199(2):185-90. [PubMed ID: 11377865]. https://doi.org/10.1111/j.1574-6968.2001.tb10672.x.
135.
Thomas CM, Timson DJ. Calmodulins from Schistosoma mansoni: Biochemical analysis and interaction with IQ-motifs from voltage-gated calcium channels. Cell Calcium. 2018;74:1-13. [PubMed ID: 29802931]. https://doi.org/10.1016/j.ceca.2018.05.006.
136.
Seukep AJ, Mbuntcha HG, Kuete V, Chu Y, Fan E, Guo MQ. What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance? Antibiotics (Basel). 2022;11(10). [PubMed ID: 36289945]. [PubMed Central ID: PMC9598416]. https://doi.org/10.3390/antibiotics11101287.
137.
Amaral L, Cerca P, Spengler G, Machado L, Martins A, Couto I, et al. Ethidium bromide efflux by Salmonella: modulation by metabolic energy, pH, ions and phenothiazines. Int J Antimicrob Agents. 2011;38(2):140-5. [PubMed ID: 21565465]. https://doi.org/10.1016/j.ijantimicag.2011.03.014.
138.
Mulkidjanian AY, Heberle J, Cherepanov DA. Protons @ interfaces: implications for biological energy conversion. Biochim Biophys Acta. 2006;1757(8):913-30. [PubMed ID: 16624250]. https://doi.org/10.1016/j.bbabio.2006.02.015.

comments

Therapeutic Mechanisms of Phenothiazine Drugs: A Mini-Review of Advances in Cancer Treatment and Antibiotic Resistance

Abstract

Context:

Evidence Acquisition:

Results:

Conclusions:

Keywords

1. Context

Structure of phenothiazine and well-known marketed phenothiazine derivatives with demonstrated anti-cancer effects

2. Evidence Acquisition

2.1. Combination Therapies with Phenothiazines: Recent Advances

2.2. Phenothiazines and Cancer: Advances in Therapeutic Mechanisms

Anti-tumor Activities and Mechanisms of Action of Phenothiazines Across Various Cancer Types

Studies Investigating Anti-Tumor Activities and the Relevant Mechanisms of Phenothiazines

2.3. Phenothiazines Induce Cell Cycle Arrest and Apoptosis in Cancer Cells

2.4. Phenothiazines Modulate Forkhead Box O Factors to Induce Cell Cycle Arrest and Apoptosis

2.5. Phenothiazines Modulate Key Signaling Pathways in Cancer Cells

2.6. Phenothiazines Inhibit Tumor Angiogenesis

2.7. Phenothiazines and the AMPK/mTOR/ULK1 Pathway in Cancer Mitophagy

2.8. Phenothiazines and Nrf2-Mediated Pathways in Oxidative Stress Modulation

2.9. Phenothiazines and Cyclooxygenase-2 Inhibitory Activity as a Possible Mechanism for Anticancer Activity

3. Results

3.1. Phenothiazines: Antibacterial Effects and Antibiotic Resistance

3.2. The Antimicrobial Action of Phenothiazines

Antibacterial Activity of Synthetic Phenothiazines by In Vitro Screening

Phenothiazines Preventive Effect Against Antibiotic Resistance and the Relevant Mechanisms

3.3. Possible Mechanisms of the Antimicrobial Action of Phenothiazines

3.4. Phenothiazines: Targeting Bacterial Membranes and Cell Wall

3.5. Phenothiazines: Targeting Nucleic Acids and Cellular Replication

3.6. Phenothiazines and Bacterial Efflux Pumps: Vital Pathway in Drug Resistance

4. Conclusions

4.1. Future Prospects and Recommendations

References

Cookie Setting