Combination Modality Using Quercetin to Enhance the Efficacy of Docetaxel in Prostate Cancer Cells

SIMPLE SUMMARY: Currently, castration-resistant prostate cancer has limited therapeutic options and is incurable after it sets in. We undertook this research to see if combination therapy with plant derived natural products are of help in overcoming the limitations of the current standard of care drug regimen. Our results indicate that a combination treatment with the natural flavonoid quercetin sensitizes the cancer cells to lower doses of the standard of care drug docetaxel, thereby reducing drug induced toxicity, and shows additive and synergistic effects with docetaxel for efficient cancer cell killing. We have identified optimum combination doses and treatment approaches for this purpose. The results of the present study provide the research community a novel therapeutic modality to enhance the efficacy of Doc in a nontoxic manner. ABSTRACT: The standard of care chemotherapy drug presently used to treat castration-resistant prostate cancer (CRPC), docetaxel (Doc), also develops chemoresistance, thereby reducing its clinical utility. Since resistance to chemotherapy drugs can be overcome by co-treatment with plant-based bio-active compounds we undertook the present study to evaluate if quercetin (Que), a flavonoid present in plants such as onions, apples, olives, and grapes can enhance the efficacy of Doc. We studied the separate and combined effects of Que and Doc at different doses and different combination approaches in two different prostate cancer cell lines, DU-145 (moderately aggressive) and PC-3 (very aggressive), and assessed the effects of these combinations on viability, proliferation, and apoptosis. Monotherapy with these drugs showed dose-dependent cytotoxicity; however, only Doc monotherapy showed a statistically significant difference in IC(50) levels (IC(50) = 4.05 ± 0.52 nM for PC-3 and IC(50) = 2.26 ± 0.22 nM for DU-145). In combination treatment, we used three different treatment approaches (TAP). The concentrations and range analyzed were chosen based on the approximate cytotoxicity of 30–50% when the drugs were used individually. Our observations indicate that the most beneficial effect of the Que and Doc combination was obtained with the TAP-2 approach, which is pre-treatment with all doses of Que for 24 h followed by low doses of Doc for another 24 h. Using this approach, we observed synergism at low concentrations of Doc (0.5 and 1.0 nM) and all concentrations of Que. An additive effect was observed at moderate and high concentrations of Doc (1.5, 2.0, and 2.5 nM) and all concentrations of Que in both cell lines. The TAP-2 strategy was also helpful in overcoming Doc resistance in resistant CaP cells. In summary, Que improved the therapeutic effect of Doc in CRPC, and it is proposed that this improvement is mediated through multiple mechanisms. This study provides a novel therapeutic modality for an effective combination using Doc and Que to enhance the efficacy of Doc in an innocuous manner for Doc resistance and CRPC treatment.