Antitumor effects of coffee diterpenes, kahweol acetate and cafestol, on taxane-resistant and neuroendocrine prostate cancer cells

Background: Epidemiological studies have reported that higher coffee consumption is associated with a reduced risk of prostate cancer. Kahweol acetate and cafestol, major diterpenes found in unfiltered coffee, have shown antitumor activity in prostate cancer cells. However, their effects on treatment-resistant subtypes, including taxane-resistant castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remain unclear. Therapeutic options for these aggressive variants remain extremely limited, highlighting the need for novel agents. We aimed to investigate the antitumor potential and underlying mechanisms of kahweol acetate and cafestol in these refractory prostate cancer models. Methods: We used docetaxel-resistant (DU145-TxR, PC-3-TxR) and cabazitaxel-resistant (DU145-TxR/CxR, PC-3-TxR/CxR) prostate cancer cell lines, which were established from their respective parental DU145 and PC-3 cells. In addition, the neuroendocrine prostate cancer cell line NCI-H660 was included. Cells were treated with kahweol acetate and/or cafestol (10-100 μM). Cell proliferation and migration were evaluated. Synergistic effects were analyzed using the combination index-isobologram method. Apoptosis induction and cell cycle distribution were evaluated by flow cytometry. Expression of apoptosis-related (cleaved-caspase-3, cleaved-PARP, Bcl-2, Bcl-xL) and EMT-related (Snail, Slug) proteins was examined by western blotting. Results: Both kahweol acetate and cafestol significantly inhibited proliferation and migration in all resistant and NEPC cell lines in a dose-dependent manner. Combined treatment (30 μM each) produced synergistic inhibition. Flow cytometry demonstrated an increased sub-G1 population and a reduced G2 phase, suggesting apoptosis induction. Western blotting revealed increased cleaved-caspase-3 and cleaved-PARP expression, along with decreased anti-apoptotic Bcl-2 and Bcl-xL levels. EMT markers Snail and Slug were also downregulated, indicating suppression of migratory potential. Conclusions: Kahweol acetate and cafestol exert strong antitumor effects in taxane-resistant and neuroendocrine prostate cancer cells through synergistic induction of apoptosis and inhibition of EMT. Given their efficacy at clinically achievable concentrations, these coffee-derived diterpenes represent promising candidates for novel therapeutic approaches in treatment-resistant prostate cancer.