Abstract
Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination of thymoquinone (TQ) with DTX and determined its cytotoxicity against PCa cells (DU145 and C4-2B). This combination, in a concentration-dependent manner, resulted in synergistic cytotoxicity and apoptosis in comparison to either DTX or TQ alone. In addition, inhibition of cell survival pathways by PI3K/AKT inhibitors conferred sensitivity of DU145 and C4-2B cells to the combination as compared to the individual drugs. Moreover, the combined drugs (DTX+TQ) with inhibitors of PI3K/AKT increased the expression of pro-apoptotic markers (BAX and BID) along with caspase-3, PARP and decreased expression of the anti-apoptotic marker, BCL-XL. These data show that, for PCa cells, the cytotoxic effect of the DTX and TQ combination correlates with a block of the PI3K/AKT signaling pathway. These findings indicate that the combination of DTX and TQ, by blocking of the PI3K/AKT pathway, will improve the survival rate and quality of life of PCa patients.
Highlights
Prostate cancer (PCa) is common in men, causing 250,000 deaths each year [1]
To determine the therapeutic potentials of TQ, DTX, and their combination, viability assays were performed for C4-2B and DU145 cells
The toxicity of TQ and DTX combined was determined in the presence of the PI3Ki and Akt inhibitor (AKTi)
Summary
Prostate cancer (PCa) is common in men, causing 250,000 deaths each year [1]. In 90% of cases, PCa is diagnosed as organ-confined or locally advanced, based on clinical stage and levels of prostate-specific antigen. PCa can be diagnosed at early stages, some patients develop metastases after local treatment with surgery/radiotherapy [2]. With these considerations, decisions are made whether to opt for active surveillance, or definitive therapy [3]. PCa that has advanced despite the achievement of castrate levels of androgens are considered as castration-resistant (CRPCs). High levels of prostate-specific antigen, substantive pain, and bone and lymph node metastases are associated with patient morbidity [4]
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