Combined Pitavastatin and Dacarbazine Treatment Activates Apoptosis and Autophagy Resulting in Synergistic Cytotoxicity in Melanoma Cells

Overview

Journal Oncol Lett

Specialty Oncology

Date 2018 Jan 19

PMID 29344241

Citations 22

Authors

Abeer Al-Qatati

Saeb Aliwaini

Affiliations

Soon will be listed here.

Abstract

Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anti-cancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma.

Citing Articles

Best of 2024 in Prostate Cancer and Prostatic diseases.

De Nunzio C Prostate Cancer Prostatic Dis. 2025; 28(1):1-5.

PMID: 39833290 DOI: 10.1038/s41391-025-00941-4.

Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions.

Ali M, Roky A, Azad S, Shaikat A, Meem J, Hoque E Cancer Pathog Ther. 2024; 2(4):231-245.

PMID: 39371094 PMC: 11447340. DOI: 10.1016/j.cpt.2024.01.002.

Molecular Mechanisms Underlying the Anticancer Properties of Pitavastatin against Cervical Cancer Cells.

Chen Y, Wu J, Yang S, Wu Y, Hsiao Y Int J Mol Sci. 2024; 25(14).

PMID: 39063157 PMC: 11277542. DOI: 10.3390/ijms25147915.

Statins as anti-tumor agents: A paradigm for repurposed drugs.

Tripathi S, Gupta E, Galande S Cancer Rep (Hoboken). 2024; 7(5):e2078.

PMID: 38711272 PMC: 11074523. DOI: 10.1002/cnr2.2078.

Exploring a repurposed candidate with dual hIDO1/hTDO2 inhibitory potential for anticancer efficacy identified through pharmacophore-based virtual screening and in vitro evaluation.

Aboomar N, Essam O, Hassan A, Bassiouny A, Arafa R Sci Rep. 2024; 14(1):9386.

PMID: 38653790 PMC: 11039737. DOI: 10.1038/s41598-024-59353-4.

References

McFarland A, Anoopkumar-Dukie S, Arora D, Grant G, McDermott C, Perkins A . Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci. 2014; 15(11):20607-37. PMC: 4264186. DOI: 10.3390/ijms151120607. View

Koprowska K, Hartman M, Sztiller-Sikorska M, Czyz M . Parthenolide enhances dacarbazine activity against melanoma cells. Anticancer Drugs. 2013; 24(8):835-45. DOI: 10.1097/CAD.0b013e3283635a04. View

Yang P, Chen C . Life or death? Autophagy in anticancer therapies with statins and histone deacetylase inhibitors. Autophagy. 2010; 7(1):107-8. DOI: 10.4161/auto.7.1.13988. View

Li W, Melton D . Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene. 2011; 31(19):2412-22. DOI: 10.1038/onc.2011.426. View

Kim Y, Brox T, Feiden W, Weickert J . Fully automated segmentation and morphometrical analysis of muscle fiber images. Cytometry A. 2007; 71(1):8-15. DOI: 10.1002/cyto.a.20334. View

Patel P, Suciu S, Mortier L, Kruit W, Robert C, Schadendorf D . Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011; 47(10):1476-83. DOI: 10.1016/j.ejca.2011.04.030. View

Yang Z, Chee C, Huang S, Sinicrope F . The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011; 10(9):1533-41. PMC: 3170456. DOI: 10.1158/1535-7163.MCT-11-0047. View

Fujino M, Miura S, Matsuo Y, Tanigawa H, Kawamura A, Saku K . Pitavastatin-induced downregulation of CCR2 and CCR5 in monocytes is associated with the arrest of cell-cycle in S phase. Atherosclerosis. 2005; 187(2):301-8. DOI: 10.1016/j.atherosclerosis.2005.10.008. View

Wang J, Tokoro T, Higa S, Kitajima I . Anti-inflammatory effect of pitavastatin on NF-kappaB activated by TNF-alpha in hepatocellular carcinoma cells. Biol Pharm Bull. 2006; 29(4):634-9. DOI: 10.1248/bpb.29.634. View

10.

Warita K, Warita T, Beckwitt C, Schurdak M, Vazquez A, Wells A . Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion. Sci Rep. 2014; 4:7593. PMC: 4274516. DOI: 10.1038/srep07593. View

11.

Lui P, Cashin R, Machado M, Hemels M, Corey-Lisle P, Einarson T . Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 2007; 33(8):665-80. DOI: 10.1016/j.ctrv.2007.06.004. View

12.

Aliwaini S, Swarts A, Blanckenberg A, Mapolie S, Prince S . A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy. Biochem Pharmacol. 2013; 86(12):1650-63. DOI: 10.1016/j.bcp.2013.09.020. View

13.

Aliwaini S, Peres J, Kroger W, Blanckenberg A, de la Mare J, Edkins A . The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells. Cancer Lett. 2014; 357(1):206-218. DOI: 10.1016/j.canlet.2014.11.027. View

14.

Simon A . Cholesterol metabolism and immunity. N Engl J Med. 2014; 371(20):1933-5. DOI: 10.1056/NEJMcibr1412016. View

15.

Ishibashi M, Arai M, Tanaka S, Onda K, Hirano T . Antiproliferative and apoptosis-inducing effects of lipophilic vitamins on human melanoma A375 cells in vitro. Biol Pharm Bull. 2012; 35(1):10-7. DOI: 10.1248/bpb.35.10. View

16.

Surova O, Zhivotovsky B . Various modes of cell death induced by DNA damage. Oncogene. 2012; 32(33):3789-97. DOI: 10.1038/onc.2012.556. View

17.

Risberg K, Fodstad O, Andersson Y . Anti-melanoma activity of the 9.2.27PE immunotoxin in dacarbazine resistant cells. J Immunother. 2010; 33(3):272-8. DOI: 10.1097/CJI.0b013e3181c54991. View

18.

Tu Y, Kang X, Zhou J, Lv X, Tang Y, Guan Y . Involvement of Chk1-Cdc25A-cyclin A/CDK2 pathway in simvastatin induced S-phase cell cycle arrest and apoptosis in multiple myeloma cells. Eur J Pharmacol. 2011; 670(2-3):356-64. DOI: 10.1016/j.ejphar.2011.09.031. View

19.

Lev D, Onn A, Melinkova V, Miller C, Stone V, Ruiz M . Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004; 22(11):2092-100. DOI: 10.1200/JCO.2004.11.070. View

20.

Fuller T, Canada R . Enhancement of cisplatin cytotoxicity by terbium in cisplatin-resistant MDA/CH human breast cancer cells. Cancer Chemother Pharmacol. 1999; 44(3):249-52. DOI: 10.1007/s002800050974. View