Document Type : Original Article

Authors

1 Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

2 Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

3 School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Background: In this study, we aimed to investigate the combined effect of sodium valproate (SV) and lithium (Li) against viability, migration, and invasion of prostate cancer cell line.
Method: In this in vitro study, PC3 cells were treated with different concentrations of SV (2.5, 5.0, and 10 mM) and Li (2.5, 5.0, and 10 µM) either alone or in combination in this in vitro investigation. Using the MTT test and annexin V/7ADD flow-cytometry, cell viability and apoptosis were assessed. Transwell chamber test was used to assess PC3 cells' invasion and migration.
Results: SV and Li alone had no significant on PC3 cell viability. However, the combination of SV and Li in all tested concentrations decreased the viability of PC3 cells in a dose dependent manner (P < 0.001). The combination of SV and Li (5.0 µM + 5.0 mM) increased apoptosis of PC3 cells compared to the control group (P = 0.003). Transwell assay showed that combination of SV with Li (5.0 µM + 5.0 mM) reduced the migration and invasion PC3 cells significantly. The lack of a significant difference between the predicted and observed fractional inhibition for the effects of SV+Li suggests that SV and Li may have synergistic effects on lowering PC3 cell viability and invasiveness.  
Conclusion: This study's findings show that combined low doses of SV and Li could decrease the viability and invasiveness of the PC3 cells; therefore, it can be considered as a new strategy for the treatment of PCa. Furthermore, in vivo studies are required to confirm the results of this study.

Keywords

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.30476/mejc.2022.93057.1676

  1. Barsouk A, Padala SA, Vakiti A, Mohammed A, Saginala K, Thandra KC, et al. Epidemiology, staging and management of prostate cancer. Med Sci (Basel). 2020;8(3):28. doi: 10.3390/medsci8030028.
  2. Nguyen DD, Berlin A, Matthew AG, Perlis N, Elterman DS. Sexual function and rehabilitation after radiation therapy for prostate cancer: a review. Int J Impot Res. 2021;33(4):410-7. doi: 10.1038/s41443-020-00389-1.
  3. Kretschmer A, Ploussard G, Heidegger I, Tsaur I, Borgmann H, Surcel C, et al. Health-related quality of life in patients with advanced prostate cancer: A systematic review. Eur Urol Focus. 2021;7(4):742-51. doi: 10.1016/j.euf.2020.01.017.
  4. Rodrigues DN, Butler LM, Estelles DL, de Bono JS. Molecular pathology and prostate cancer therapeutics: from biology to bedside. J Pathol. 2014;232(2):178-84. doi: 10.1002/path.4272.
  5. Sathianathen NJ, Koschel S, Thangasamy IA, Teh J, Alghazo O, Butcher G, et al. Indirect comparisons of efficacy between combination approaches in metastatic hormone-sensitive prostate cancer: a systematic review and network meta-analysis. Eur Urol. 2020;77(3):365-72. doi: 10.1016/j.eururo.2019.09.004.
  6. Zarei MA, Dehbidi GR, Takhshid MA. Combination of NDRG2 overexpression, X-ray radiation and docetaxel enhances apoptosis and inhibits invasiveness properties of LNCaP cells. Urol Oncol. 2020;38(11):849.e1-849.e9. doi: 10.1016/j.urolonc.2020.06.017.
  7. Verza FA, Das U, Fachin AL, Dimmock JR, Marins M. Roles of histone deacetylases and inhibitors in anticancer therapy. Cancers (Basel). 2020;12(6):1664. doi: 10.3390/cancers12061664.
  8. Ribatti D, Tamma R. Epigenetic control of tumor angiogenesis. Microcirculation. 2020;27(3):e12602. doi: 10.1111/micc.12602.
  9. Song Y, Shiota M, Tamiya S, Kuroiwa K, Naito S, Tsuneyoshi M. The significance of strong histone deacetylase 1 expression in the progression of prostate cancer. Histopathology. 2011;58(5):773-80. doi: 10.1111/j.1365-2559.2011.03797.x.
  10. Suenaga M, Soda H, Oka M, Yamaguchi A, Nakatomi K, Shiozawa K, et al. Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells. Int J Cancer. 2002;97(5):621-5. doi: 10.1002/ijc.10082.
  11. Qian X, Ara G, Mills E, LaRochelle WJ, Lichenstein HS, Jeffers M. Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer. 2008;122(6):1400-10. doi: 10.1002/ijc.23243.
  12. Li B, Thrasher JB, Terranova P. Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. Urol Oncol. 2015;33(11):456-63. doi: 10.1016/j.urolonc.2015.05.006.
  13. Edderkaoui M, Chheda C, Soufi B, Zayou F, Hu RW, Ramanujan VK, et al. An inhibitor of GSK3B and HDACs kills pancreatic cancer cells and slows pancreatic tumor growth and metastasis in mice. Gastroenterology. 2018;155(6):1985-98.e5. doi: 10.1053/j.gastro.2018.08.028.
  14. Adler JT, Hottinger DG, Kunnimalaiyaan M, Chen H. Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride. J Surg Res. 2010;159(2):640-4.  doi: 10.1016/j.jss.2008.08.004.
  15. Michaelis M, Doerr HW, Cinatl J Jr. Valproic acid as anti-cancer drug. Curr Pharm Des. 2007;13(33):3378-93.
  16. Saberzadeh J, Omrani M, Takhshid MA. Protective effects of nimodipine and lithium against aluminum-induced cell death and oxidative stress in PC12 cells. Iran J Basic Med Sci. 2016;19(11):1251-7.
  17. Foucquier J, Guedj M. Analysis of drug combinations: current methodological landscape. Pharmacology research & perspectives. Pharmacol Res Perspect. 2015;3(3):e00149. doi: 10.1002/prp2.149.
  18. Baldo BA, Pham NH. Targeted drugs for cancer therapy: Small molecules and monoclonal antibodies. Pharmacol Res Perspect.  2015;3(3):e00149. doi: 10.1002/prp2.149.
  19. Mokhtari RB, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022-43. doi: 10.18632/oncotarget.16723.
  20. Rana Z, Diermeier S, Hanif M, Rosengren RJ. Understanding failure and improving treatment using HDAC inhibitors for prostate cancer. Biomedicines. 2020;8(2):22. doi: 10.3390/biomedicines8020022.
  21. Tavora F, Lotan T, Alves M, Zhou L, Amin A, Arunasalam N, et al. Glycogen synthase kinase 3-β expression in prostate cancer (PCa) correlates with aggressive pathological features and its blockade with 9-ING-41 inhibits viability of PCa cell lines. Cancer Res. 2020;80(16_Supplement): 2959. doi: 10.1158/1538-7445.AM2020-2959.
  22. Furuta T, Sabit H, Dong Y, Miyashita K, Kinoshita M, Uchiyama N, et al. Biological basis and clinical study of glycogen synthase kinase-3β-targeted therapy by drug repositioning for glioblastoma. Oncotarget. 2017;8(14):22811-24. doi: 10.18632/oncotarget.15206.
  23. Erguven M, Oktem G, Kara AN, Bilir A. Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels. Oncol Lett. 2016;12(4):2948-55. doi: 10.3892/ol.2016.4946.
  24. Azimian-Zavareh V, Hossein G, Janzamin E. Effect of lithium chloride and antineoplastic drugs on survival and cell cycle of androgen-dependent prostate cancer LNCap cells. Indian J Pharmacol. 2012;44(6):714-21. doi: 10.4103/0253-7613.103265.
  25. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30(1):87. doi: 10.1186/1756-9966-30-87.
  26. Kaufmann L, Marinescu G, Nazarenko I, Thiele W, Oberle C, Sleeman J, et al. LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells. Cell Commun Signal. 2011;9:15. doi: 10.1186/1478-811X-9-15.
  27. Angelucci A, Valentini A, Millimaggi D, Gravina GL, Miano R, Dolo V, et al. Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathways. Anticancer Drugs. 2006;17(10):1141-50. doi: 10.1097/01.cad.0000236302.89843.fc.
  28. Cunningham D, You Z. In vitro and in vivo model systems used in prostate cancer research. J Biol Methods. 2015;2(1):e17. doi: 10.14440/jbm.2015.63.
  29. Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer. 2011;2(4):466-74. doi: 10.1177/1947601911408889.
  30. Kiani A, Kamankesh M, Vaisi-Raygani A, Moradi MR, Tanhapour M, Rahimi Z, et al. Activities and polymorphisms of MMP-2 and MMP-9, smoking, diabetes and risk of prostate cancer. Mol Biol Rep. 2020;47(12):9373-83. doi: 10.1007/s11033-020-05968-5.
  31. Medina-González A, Eiró-Díaz N, Fernández-Gómez JM, Ovidio-González L, Jalón-Monzón A, Casas-Nebra J, et al. Comparative analysis of the expression of metalloproteases (MMP-2, MMP-9, MMP-11 and MMP-13) and the tissue inhibitor of metalloprotease 3 (TIMP-3) between previous negative biopsies and radical prostatectomies. Actas Urol Esp. 2020;44(2):78-85. doi: 10.1016/j.acuro.2019.10.004.
  32. Melegh Z, Oltean S. Targeting angiogenesis in prostate cancer. Int J Mol Sci. 2019;20(11):2676. doi: 10.3390/ijms20112676.
  33. Afzal E, Alinezhad S, Khoshnood MJ, Takhshid MA. Effects of two-by-two combination therapy with valproic acid, lithium chloride, and celecoxib on the angiogenesis of the chicken chorioallantoic membrane. Iran J Med Sci. 2018;43(5):506-13.