Induction of apoptotic and anti-proliferative effects in REH cells upon neurokinin-1 receptor inhibition using Aprepitant

authors:

avatar Elham Razani , avatar A. va Safaroghli-Azar , avatar Davood Bashash , *


how to cite: Razani E, Safaroghli-Azar A V, Bashash D. Induction of apoptotic and anti-proliferative effects in REH cells upon neurokinin-1 receptor inhibition using Aprepitant. koomesh. 2018;20(4):e153022. 

Abstract

Introduction: Following the first description of neurokinin-1 receptor (NK1R) network as a carcinogenic pathway, overwhelming numbers of studies have reported the inappropriate activity of this cascade in a wide assortment of human cancers. On the basis of the principal importance of NK1R in the pathogenesis of acute lymphoblastic leukemia (ALL), it was of great interest to dissect the effect of Aprepitant, a competing non-peptide NK1R antagonist, on REH Pre-B ALL cells. Materials and Methods: To evaluate the anti-leukemic effect of NK1R antagonist, REH cells were exposed to the increasing concentrations of Aprepitant and subsequent cell viability, growth kinetics, and metabolic activity were investigated. Moreover, to underscore whether Aprepitant-induced cytotoxic effect could be attributed to either induction of apoptosis or cell cycle arrest, Annexin-V/PI staining and DNA content analysis were performed. Finally, the transcriptional alterations of apoptosis-related target genes were studied using RQ-PCR. Results: Intrestingly, we found that abrogation of the NK1R signaling pathway exerts cytotoxic and anti-proliferative effects against REH cells, as evidenced by the increased externalization of phosphatidyl serine (PS), elevated G1 cell population, and decreased number of inhibitor-treated viable cells. In addition, our results also suggested that Aprepitant-induced apoptotic cell death in REH cells is mediated, at least partially, through shifting the ratio of death promoters to death repressors via alteration of Bax and Bcl2 expression. Conclusion: This study highlighted the potent efficacy of Aprepitant in Pre-B ALL cells and shed light on pro-apoptotic property of this inhibitor.  

References

  • 1.

    Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Educ Program 2013; 2013: 118-125.

  • 2.

    Hinze L, Mricke A, Zimmermann M, Junk S, Cario G, Dagdan E, et al. Prognostic impact of IKZF1 deletions in association with vincristinedexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95. Leukemia 2017; 31: 1840-1842.

  • 3.

    Esteban F, Munoz M, Gonzalez-Moles M, Rosso M. A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev 2006; 25: 137-145.

  • 4.

    Munoz M, Rosso M, Coveas R. The NK-1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on human pancreatic cancer cell lines. Lett Drug Design Discov 2006; 3: 323-329.

  • 5.

    Akazawa T, Kwatra SG, Goldsmith LE, Richardson MD, Cox EA, Sampson JH, et al. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptormediated apoptosis in glioblastomas. J Neurochem 2009; 109: 1079-1086.

  • 6.

    Munoz M, Rosso M, Prez A, Covenas R, Rosso R, Zamarriego C, et al. Antitumoral action of the neurokinin-1-receptor antagonist L-733,060 and mitogenic action of substance P on human retinoblastoma cell lines. Invest Ophthalmol Vis Sci 2005; 46: 2567-2570.

  • 7.

    Muoz M, Gonzlez-Ortega A, Coveas R. The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines. Invest New Drugs 2012; 30: 529-540.

  • 8.

    Grassin-Delyle S, Buenestado A, Vallat L, Naline E, Marx S, Decocq J, et al. Expression and proliferative effect of hemokinin-1 in human B-cells. Peptides 2011; 32: 1027-1034.

  • 9.

    Quartara L, Altamura M, Evangelista S, Maggi CA. Tachykinin receptor antagonists in clinical trials. Expert Opin Investig Drugs 2009; 18: 1843-1864.

  • 10.

    Aapro M, Carides A, Rapoport BL, Schmoll H-J, Zhang L, Warr D. Aprepitant and fosaprepitant: a 10-year review of efficacy and safety. Oncologist 2015; 20: 450-458.

  • 11.

    Muoz M, Rosso M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest New Drugs 2010; 28: 187-193.

  • 12.

    Muoz M, Gonzlez-Ortega A, Salinas-Martn MV, Carranza A, Garcia-Recio S, Almendro V, et al. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int J Oncol 2014; 45: 1658-1672.

  • 13.

    Nakade S, Ohno T, Kitagawa J, Hashimoto Y, Katayama M, Awata H, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 2008; 63: 75-83.

  • 14.

    Kast RE, Ramiro S, Llad S, Toro S, Coveas R, Muoz M. Antitumor action of temozolomide, ritonavir and aprepitant against human glioma cells. J Neurooncol 2016; 126: 425-431.

  • 15.

    Garnier A, Ilmer M, Kappler R, Berger M. Therapeutic Innovations for Targeting Hepatoblastoma. Anticancer Res 2016; 36: 5577-5592.

  • 16.

    Garnier A, Vykoukal J, Hubertus J, Alt E, Von Schweinitz D, Kappler R, et al. Targeting the neurokinin-1 receptor inhibits growth of human colon cancer cells. Int J Oncol 2015; 47: 151-160.

  • 17.

    Muoz M, Coveas R. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach. Saudi J Gastroenterol 2016; 22: 260-268.

  • 18.

    Muoz M, Berger M, Rosso M, Gonzalez-Ortega A, Carranza A, Coveas R. Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts. Int J Oncol 2014; 44: 137-146.

  • 19.

    Bayati S, Bashash D, Ahmadian S, Safaroghli-Azar A, Alimoghaddam K, Ghavamzadeh A, et al. Inhibition of tachykinin NK 1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells. Eur J Pharmacol 2016; 791: 274-283.

  • 20.

    Bayati S, Razani E, Bashash D, Safaroghli-Azar A, Safa M, Ghaffari SH. Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant. Anticancer Drugs 2018; 29: 243-252.

  • 21.

    Kryvenko ON, Williamson SR, Trpkov K, Gupta NS, Athanazio D, Selig MK, et al. Small cell-like glandular proliferation of prostate: a rare lesion not related to small cell prostate cancer. Virchows Arch 2017; 470: 47-54.