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Possible Anticancer Activity of Rosuvastatine, Doxazosin, Repaglinide and Oxcarbazepin

  • Published : 2014.01.15

Abstract

Background: Rosuvastatine, doxazosin, repaglinide and oxcarbazepin are therapeutic drugs available in the market for the treatment of different diseases. Potential to display antitumor activities has also been suggested. The aim of the current study was to evaluate their in vitro effects on some human transformed cell lines. Materials and Methods: Cytotoxicity of the four drugs was tested in MCF-7, HeLa and HepG2 cells by the neutral red assay method and also the effect of rosuvastatine and doxazosin against Ehrlich Ascities Carcinoma Cells (EACC) by trypan blue assay. Results: Rosuvastatine exerted the greatest cytotoxic effect against HepG2 cells with an $IC_{50}$ value of $58.7{\pm}69.3$; in contrast doxazosin showed least activity with $IC_{50}=104.4{\pm}115.7$. Repaglinide inhibited the growth of both HepG2 and HeLa cells with $IC_{50}$ values of $87.6{\pm}117.5$ and $89.3{\pm}119.5$, respectively. Oxcarbazepine showed a potent cytotoxicity against both HeLa ($IC_{50}=19.4{\pm}43.9$) and MCF7 cancer cells (($IC_{50}=22{\pm}35.7$).On the other hand the growth of EACC was completely inhibited by doxazosine (100% inhibition) while rosuvastatine had weak inhibitory activity (11.6%). Conclusions: The four tested drugs may have cytotoxic effects against hepatic, breast and cervical carcinoma cells; also doxazosine may inhibit the growth of endometrial cancer cells. Further investigations in animals are needed to confirm these results.

Keywords

References

  1. Aguilar-Salinas CA, Barrett H, Schonfeld G ( 1993). Metabolic modes ofaction of the statins in the hyperlipoproteinemias. Atherosclerosis, 141, 203-7.
  2. Arencibia JM, Del Rio M, Bonnin A, et al (2005). Doxazosin induces apoptosis in LNCaP prostate cancer cell line through DNA binding and DNA-dependent protein kinase downregulation. Int J Oncol, 27, 1617-23.
  3. Bader T, Fazili J, Madhoum M, et al (2008). Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol, 103, 1383-9. https://doi.org/10.1111/j.1572-0241.2008.01876.x
  4. Bennett JM, Catovsky D, Danniel MT, et al (1976). Proposal for the classification of the acute leukemia. Br J Heam, 33, 451-8. https://doi.org/10.1111/j.1365-2141.1976.tb03563.x
  5. Campos-Lara M and Mendoza-Espinoza JA (2011). Cytotoxic evaluation of fluvastatin and rosuvastatin and effect of fluvastatin in the hela cell cycle. African J Pharm Pharmacol, 5, 189-93. https://doi.org/10.5897/AJMR10.342
  6. Cansu A, Erdogan D, Serdaroglu A, et al (2010). Histologic and morphologic effects of valproic acid and oxcarbazepine on rat uterine and ovarian cells. Epilepsia, 51, 98-107.
  7. Chan KWK, Oza MA, Siu LL (2003). The statins as anticancer agents. Clin Cancer Res, 9, 10-19.
  8. Chiang CF, Son EL,Wu GJ (2005). Oral treatment of the TRAMP mice with doxazosin suppresses prostate tumor growth and metastasis. Prostate, 64, 408-18. https://doi.org/10.1002/pros.20260
  9. Feng YH, Velazquez-Torres G, Gully C, et al (2011). The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med, 15, 825-36. https://doi.org/10.1111/j.1582-4934.2010.01083.x
  10. Garrison JB, Kyprianou N (2006). Doxazosin induces apoptosis of benign and malignant prostate cells via a death receptormediated pathway. Cancer Res, 66, 464-72. https://doi.org/10.1158/0008-5472.CAN-05-2039
  11. Gan L, Zhu DX, Yang LP, et al (2008). Involvement of transcription factor activator protein-2alpha in doxazosininduced HeLa cell apoptosis. Acta Pharmacol Sin, 29, 465-72. https://doi.org/10.1111/j.1745-7254.2008.00780.x
  12. Ghosh-Choudhury N, Mandal CC, Ghosh-Choudhury G (2010). Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell growth. Cell Signal, 22, 749-58. https://doi.org/10.1016/j.cellsig.2009.12.010
  13. Glozak MA, Seto E (2007). Histone deacetylases and cancer. Oncogene, 26, 5420-32. https://doi.org/10.1038/sj.onc.1210610
  14. Hui H, Fernando MA, Heaney AP (2008). The alpha1-adrenergic receptor antagonist doxazosin inhibits EGFR and NFkappaB signaling to induce breast cancer cell apoptosis. Eur J Cancer, 44, 160-6. https://doi.org/10.1016/j.ejca.2007.10.002
  15. Landgraf R (2000). Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging, 17, 411-25. https://doi.org/10.2165/00002512-200017050-00007
  16. Nielsen SF, Nordestgaard B G, Bojesen SE (2012). Statin use and reduced cancer-related mortality. N Engl J Med, 367, 1792-802. https://doi.org/10.1056/NEJMoa1201735
  17. Partin JV, Anglin IE, Kyprianou N (2003). Quinazoline-based a1 adrenoceptor antagonists induce prostate cancer cell apoptosis viaTGF-b signaling and I kappa B a induction. Br J Cancer, 88, 1615-21. https://doi.org/10.1038/sj.bjc.6600961
  18. Qian X, Li J, Ding Jm, et al (2008).Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803. Biochem Pharmacol, 76, 1705-15. https://doi.org/10.1016/j.bcp.2008.09.009
  19. Repetto G, Peso A, Zurita J (2008). Neutral red uptake assay for the estimation of cell viability /cytotoxicity. Nature Protocols, 3, 1125-31. https://doi.org/10.1038/nprot.2008.75
  20. Seo M, Inoue I, Ikeda M, et al (2008). Statins activate human PPAR promoter and increase PPAR mRNA expression and activation in HepG2 cells. PPAR-Res, 2008, 11.
  21. Shaw YJ, Yang YT, Garrison JB, et al (2004). Pharmacological exploitation of the a1-adrenoreceptor antagonist doxazosin to develop a novel class of antitumor agents that block intracellular protein kinase B/Akt activation. J Med Chem, 47, 4453-62. https://doi.org/10.1021/jm049752k
  22. Stettner M, Kramer G, Strauss A, et al (2012). Long-term antiepileptic treatment with histone deacetylase inhibitors may reduce the risk of prostate cancer. Eur J Cancer Prev, 21, 55-64. https://doi.org/10.1097/CEJ.0b013e32834a7e6f
  23. Takahashi HK, Weitz-Schmidt G, Iwagaki H, et al (2006). Hypothesis: The antitumor activities of statins may be mediated by IL18. J Leukoc Biol, 80, 215-6. https://doi.org/10.1189/jlb.0406245
  24. Traxler P (2003). Tyrosine kinases as targets in cancer therapy-successes and failures. Expert Opin Ther Targets, 7, 215-34. https://doi.org/10.1517/14728222.7.2.215
  25. Walden PD, Globina Y, Nieder A (2004). Induction of anoikis by doxazosin in prostate cancer cells is associated with activation of caspase 3 and a reduction of focal adhesion kinase. Urol Res, 32, 261-5. https://doi.org/10.1007/s00240-003-0365-7

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