Aims: Metastatic castration-resistant prostate cancer (mCRPC) continues to be a global health issue for men, with a five-year survival rate of 36%. A standard treatment for mCRPC is chemotherapy (docetaxel), which is increasingly ineffective due to severe side effects and treatment resistance. Hence, research is needed to identify novel compounds that can be combined with docetaxel to enhance efficacy. The first aim of this study was to evaluate the cytotoxic effects of plant-derived compounds on both an androgen-sensitive and castration-resistant mPCa cell line. After identifying 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) and 18ß-glycyrrhetinic acid (GA)as the two most potent compounds, the second aim was to investigate their potential synergism with docetaxel.
Methods: The androgen-dependent LNCaP cells and the androgen-independent PC-3 cells were used. Cell viability was indirectly determined using the resazurin reduction assay to measure cellular metabolic activity. Brightfield microscope images were also used to interpret morphology changes. Dose-response curves were generated using GraphPad Prism to compare each compound’s half-maximal inhibitory concentrations (IC50) after 24, 48 and 72-hour incubations. Classic isobolograms were generated using CompuSyn and SiCoDEA to assess drug interactions. Experiments were performed with three or four biological repeats, each in triplicate. Data was analysed using a one-way ANOVA with either Dunnett’s post-hoc test (dose-response curves) or Tukey’s post-hoc test (combinations).
Results: 6-MITC and GA exhibited the greatest cytotoxic activity, with IC50 values of approximately 20µM and 100µM after 48 hours of incubation, respectively. Combinations of 6-MITC+docetaxel and GA+docetaxel showed a slight synergistic interaction between GA and docetaxel at the highest combinatorial dose, while all other combinations revealed antagonistic interactions.
Conclusion: While 6-MITC and GA were effective as single-agent cytotoxic agents, they did not provide clinically meaningful results when combined with docetaxel. Further research should analyse the anti-cancer mechanisms of 6-MITC and its combinations with other standard mCRPC treatments, like enzalutamide.