SYNERGISTIC CYTOTOXIC EFFECT OF STATINS AND BISPHOSPHONATES ON SQUAMOUS CELL CARCINOMA CELL LINE

  • Dina Sabry Abd-el-fattah Professor of Biochemistry, Faculty of Medicine, Cairo University
  • Marwa Mohammed Ellithy Researcher of Oral Pathology, Basic Dental Sciences Department, National Research Centre
  • Riham Mohammed Aly Researcher of Oral Biology, Basic Dental Sciences Department, National Research Centre

Abstract

Objective: The present study aimed at evaluating the in vitro cytotoxic effect of simvastatin (sv) and alendronate (aln) on squamous cell carcinoma cell line (Hep-2 cells).

Methods: Hep-2 cells were divided into four groups; Control group where cells were cultured in the routine culture medium. Alendronate Group (A) consisting of cells cultured in aln in its IC 50. Simvastatin Group(S) cultured in sv in its IC 50. And finally, a combined group (A+S) comprising cells cultured in combined IC 50 dose of sv and aln. To assess the effect of these drugs on Hep-2 cells, cell viability was measured in addition to measuring vascular endothelial growth factor (VEGF) expression by Elisa.

Results: In all groups, a decrease in the mean viability percentages of the treated Hep-2 cells in relation to control cells was observed in all groups. The combination of both agents exhibited a significant (P-values Ë‚0.05) synergistic effect on decreasing cell viability and angiogenesis of Hep-2 cells in vitro. VEGF measures in all groups were significantly lower than the control group (P-values Ë‚ 0.05). The combination of both drugs at their IC 50 doses can lower the VEGF production by Hep-2 cancer cells (P-values Ë‚ 0.05).

Conclusion: A combination of sv and aln in their Ic50 doses has a dramatic effect on lowering the proliferation and VEGF expression in Hep-2 cancer cells cultured in vitro.

Keywords: Cancer, Chemotherapy, Mevalonate pathway, Statins, Bisphosphonates, Angiogenesis, Cell viability, Cytotoxicity

Downloads

Download data is not yet available.

References

1. Thomas N S., Laura M S.: Cancer as a metabolic disease. Seyfried and Shelton Nutrition & Metabolism; 2010.
2. Mehrotra R. and Yadav S.: Oral squamous cell carcinoma: Etiology, pathogenesis and prognostic value of genomic alterations. Indian Journal of Cancer; 2006: 60-66.
3. Parkin D., Bray F, Ferlay J and Pisani P.: Global cancer statistics, 2002. Canadian Cancer J Clin. 2005; 55: 74-108.
4. Rousseau A. and Badoual C.: Head and Neck: Squamous cell carcinoma: an overview. Atlas Genet Cytogenet Haematol. 2012Oncol; 16: 145-155.
5. The statins as anticancer agents, 2003. Clinical cancer research.
6. Statins: Perspectives in cancer therapeutics, 2013. Digestive and Liver disease.
7. Potential mechanism of the antiproliferative effects of HMGCOA reductase inhibitors.
8. Targeting the mevalonate pathway for improved anticancer terapy, 2009.
9. Antitumor effects of Bisphosphonates: Promising preclinical Evidence.
10. Antitumor Effects and anticancer applications of bisphosphonates.
11. Direct and Indirect anticance activity of bisphosphonates: A brief review of published literature.
12- Mackie PS, Fisher JL, Zhou H and Choong PFM: Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line. Br J Cancer 84:
951-958, 2001.
13. Sonnemann J, Eckervogt V, Truckenbrod B, Boos J, Winkelmann W and van Valen F: The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro. Anticancer Drugs 12: 459-465, 2001.
14- Fromigue O, Lagneaux L and Body JJ: Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15: 2211-2221, 2000.
15- Reinholz GG, Getz B, Sanders ES, Karpeisky MY, Padyukova NS, Mikhailov SN, Ingle JN and Spelsberg TC: Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue. Breast Cancer Res Treat 71: 257-268, 2002
16- Lee MV, Fong EM, Singer FR and Guenette RS: Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 61: 2602-2608, 2001.
17 -Takahashi R, Shimazaki C, Inaba T, Okano A, Hatsuse M, Okamoto A, Hirai H, Ashihara E and Nakagawa M: A newly developed bisphosphonate, YM529, is a potent apoptosis inducer of human myeloma cells. Leuk Res 25: 77-83, 2001.
18- Riebeling C, Forsea AM, Raisova M, Orfanos CE and Geilen CC: The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. Br J Cancer 87: 366-371, 2002.
19- Vorotnjak M, Boos J and Lanvers-Kaminsky C: In vitro toxicity of bisphosphonates on human neuroblastoma cell lines. Anticancer Drugs 15: 795-802, 2004.

23. Mazieres J, Tillement V, Allal C, Clanet C, Bobin L, Chen Z, Sebti SM, Favre G and Pradines A: Geranylgeranylated, but not farnesylated, RhoB suppresses Ras transformation of NIH-3T3 cells. Exp Cell Res 304: 354-364, 2005.
24. . Muller S1, Migianu E, Lecouvey M, Kraemer M, Oudar O.: Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro. Anticancer Res. 2005; 25: 2655- 60.
25. Farese JP1, Ashton J, Milner R, Ambrose LL, Van Gilder J.: The effect of the bisphosphonate alendronate on viability of canine osteosarcoma cells in vitro. In Vitro Cell Dev Biol Anim. 2004 Mar-Apr;40(3-4):113-7.
26. Menter DG, Ramsauer VP, Harirforoosh S, Chakraborty K, Yang P, Hsi L, Newman RA and Krishnan K: Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites. PLoS One 6: e28813, 2011.
27. Hongtau Wu, , Hao Jiang, Dunyue Lu, MD3, Ye Xiong, MD, Changsheng
Qu, , Dong Zhao, , Asim Mahmood, , and Michael Chopp: Effect of Simvastatin on Glioma Cell Proliferation, Migration and Apoptosis. Neurosurgery. 2009 December ; 65: 1087–1097.
28. Xie K, Wei D, Shi Q, Huang S. Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev. 2004; 15:297–324.
29. GreenJR. Bisphosphonates: preclinical review. Oncologist. 2004;9:3–13.

30. Takenaka M, Hirade K, Tanabe K, Akamatsu S, Dohi S, Matsuno H, Kozawa O. Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells. Biochem Biophys Res Commun. 2003; 301:198–203.

31. Siddiqui AJ, Gustafsson T, Fischer H, Widegren U, Hao X, Mansson-Broberg A, Grinnemo KH, Dellgren G, Sylven C. Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer. J Mol Cell Cardiol. 2004; 37:1235–1244

32. Synergistic growth inhibition of PC3 prostate cancer cells with low dose combinations of Simvastatin and Alendronate, 2015. Anticancer research.
33. Synergistic antimyeloma effects of zolendronate and simvastatin.
34. Statins may potentiate bisphosphonates anticancer properties, 2003. Medical Hypotheses
35. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L and Zamvil SS: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78-84, 2002.
36. Hilgendorff A, Muth H, Parviz B, Staubitz A, Haberbosch W, Tillmanns H and Holschermann H: Statins differ in their ability to block NF-kappaB activation in human blood monocytes. International journal of clinical pharmacology and therapeutics
41: 397-401, 2003.
37. Tilkin-Mariame AF, Cormary C, Ferro N, Sarrabayrouse G, Lajoie-Mazenc I, Faye JC and Favre G: Geranylgeranyl transferase inhibition stimulates anti-melanoma immune response through MHC Class I and costimulatory molecule expression. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 19: 1513-1515, 2005.
38. Rao S, Porter DC, Chen X, Herliczek T, Lowe M and Keyomarsi K: Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci USA 96: 7797-7802, 1999.
39. Veillard NR and Mach F: Statins: the new aspirin? Cellular andmolecular life sciences: CMLS 59: 1771-1786, 2002.
37. Weis M, Heeschen C, Glassford AJ and Cooke JP: Statins have biphasic effects on angiogenesis. Circulation 105: 739-745, 2002.
40. Shibata MA, Ito Y, Morimoto J and Otsuki Y: Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrial-mediated apoptotic mechanism. Carcinogenesis 25: 1887-1898, 2004. ANTICANCER RESEARCH 35: 1851-1860 (2015)1858
41. Macaulay RJ, Wang W, Dimitroulakos J, Becker LE and Yeger H: Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. Journal of neuro-oncology 42: 1-11, 1999.
Statistics
238 Views | 765 Downloads
Citatons
How to Cite
Abd-el-fattah, D. S., M. M. Ellithy, and R. M. Aly. “SYNERGISTIC CYTOTOXIC EFFECT OF STATINS AND BISPHOSPHONATES ON SQUAMOUS CELL CARCINOMA CELL LINE”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 9, no. 8, Aug. 2017, pp. 123-7, doi:10.22159/ijpps.2017v9i8.19436.
Section
Original Article(s)