Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU-145 human prostate cancer cells by modulating PI3K–AKT pathway
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The treatment of castrate-resistant prostate cancer (CRPC) still remains as an important challenge of daily oncology practice. Docetaxel significantly prolongs overall survival in men with CRPC. Thymoquinone (TQ), one of the flavonoid compounds isolated from Nigealla sativa, has been shown to possess cytotoxic activity against a variety of cancer cell lines.
Materials and Methods
The aim of the study was to investigate the possible synergistic cytotoxic/apoptotic effects of a novel combination, docetaxel and TQ in DU-145 hormone- and drug-refractory prostate cancer cells and their effects on PI3K and ERK signaling pathways.
We observed that the combination of docetaxel and TQ resulted in a significant synergistic cytotoxicy and apoptosis as compared to any single agent alone, in a dose-dependent manner. It was found that viability of the combination treated cells was not significantly changed in the presence of LY294002 as compared to inhibitor treated cells. However, in the presence of FR180204, viability of combination treated cells was significantly decreased as compared to inhibitor treated cells. In conclusion, cytotoxic effect of the docetaxel and TQ combination is correlated with the block of the PI3K/Akt signaling pathway in DU-145 cells.
Therefore, this combination strategy may be an alternative approach for the challenging era of daily oncologic practice. Also, the combination of docetaxel and TQ might allow a reduction in docetaxel doses and diminish adverse effects of docetaxel while maintaining the therapeutic effect in patients with CRPC.
KeywordsThymoquinone Docetaxel Prostate cancer Combination treatment PI3K/Akt signaling pathways
- 1.Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W et al. SEER cancer statistics review, 1975–2008. National Cancer Institute: Bethesda. http://seer.cancer.gov/csr/1975_2008/. Accessed 28 March 2013.
- 5.Basch EM, Somerfield MR, Beer TM, Carducci MA, Higano CS, Hussain MH, et al. American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on non hormonal therapy for men with metastatic hormone-refractory (castration resistant) prostate cancer. J Clin Oncol. 2007;25(33):5313–8.PubMedCrossRefGoogle Scholar
- 7.Picus J, Halabi S, Rini B. The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: initial results of CALGB 90006. J Clin Oncol. 2003;22(Supp l):393 (Abstr 1578).Google Scholar
- 8.Salzberg M, Rochlitz C, Morant R, Thalmann G, Pedrazzini A, Roggero E, et al. An open-label, noncomparative phase II trial to evaluate the efficacy and safety of docetaxel in combination with gefitinib in patients with hormone-refractory metastatic prostate cancer. Onkologie. 2007;30(7):355–60.PubMedCrossRefGoogle Scholar
- 9.Quinn DI, Tangen CM, Hussain M, Lara PN Jr, Goldkorn A, Moinpour CM, et al. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013;14(9):893–900. doi:10.1016/S1470-2045(13)70294-8.PubMedCentralPubMedCrossRefGoogle Scholar
- 10.Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, et al. VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013;14:760–8. doi:10.1016/S1470-2045(13)70184-0.PubMedCrossRefGoogle Scholar
- 21.Zubair H, Khan HY, Sohail A, Azim S, Ullah MF, Ahmad A, et al. Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants. Cell Death Dis. 2013. doi:10.1038/cddis.2013.172.PubMedCentralPubMedGoogle Scholar
- 24.Yoshimoto M, Cutz JC, Nuin PA, Gilbert C, Coffer P, Downward J, et al. Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23 % of high-grade prostatic intra-epithelial neoplasias. Cancer Genet Cytogenet. 2006;169(2):128–37.PubMedCrossRefGoogle Scholar
- 29.Nomura T, Yamasaki M, Hirai K, Inoue T, Sato R, Matsuura K, et al. Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia. Mol Cancer. 2013;12:27. doi:10.1186/1476-4598-12-27.PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Qiu Y, Robinson D, Pretlow TG, Kung HJ. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3′-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci USA. 1998;95(7):3644–9.PubMedCentralPubMedCrossRefGoogle Scholar