Simultaneous Autophagy and Androgen Receptor Inhibition in a Prostate Cancer Xenograft Model.

Simple Summary: Recent advancements in anticancer drug treatments face significant challenges due to drug resistance, often leading to only partial or short-term responses in patients. Our previous in vitro studies indicated that autophagy is linked to drug resistance in prostate cancer (PCa). Consequently, combination therapies targeting multiple pathways could help overcome resistance and extend treatment efficacy. To validate our earlier findings, we conducted in vivo experiments. Our data demonstrated that combining Abiraterone (Abi) with an autophagy inhibitor such as Chloroquine (Chl) not only reduces autophagy but also suppresses tumors more effectively than Abi alone. Thus, the combination of Abi with autophagy inhibitors represents a promising therapeutic strategy that could potentially offer a novel approach for patients. Objective: Abi, when used in conjunction with prednisone, is an established treatment for advanced PCa. Our goal was to explore the level of autophagy induced by Abi treatment, both alone and in combination with the autophagy inhibitor Chl, in a castrated mouse xenograft model. Methods: LNCaP cells were injected into the left and right sides of the back of nude mice that had been previously castrated. Mice were divided into four groups and treated daily with intraperitoneal injections of vehicle (control), Abi (10 mg/kg), Abi (10 mg/kg) combined with Chl (10 mg/kg), or Chl (10 mg/kg), and were monitored for periods of 2 and 3 weeks. Results: A significant reduction in tumor weight was observed in mice treated with the combination therapy, as opposed to those receiving vehicle control, Abi, or Chl alone. Mice receiving Abi + Chl exhibited reduced expression of ATG5, Beclin 1, and LC3 punctuations, along with an increase in P62, as determined by immunofluorescence and WES analysis. AR expression decreased significantly in all treatment groups compared to the control. PSMA expression was highest in the vehicle and combined treatment groups after 3 weeks, with a significant reduction observed with Chl treatment. Conclusions: These findings demonstrate that Abi + Chl treatment lowers autophagy levels and suppresses tumors more effectively than Abi alone. [ABSTRACT FROM AUTHOR]