Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer.

BACKGROUND: Corosolic acid (CA) and its derivatives have shown promise as anticancer agents, but their effectiveness against resistant cancer types remains underexplored. Organelle-targeted drug delivery is a promising approach to enhance therapeutic efficacy and reduce side effects. METHODS: A mitochondria-targeted prodrug, CA-TPP, was synthesized using an esterase-responsive phenolic ester bond, which enables the in situ release of CA within the mitochondria. The therapeutic efficacy of CA-TPP was assessed both in vitro (using DU145 cells) and in vivo. RNA sequencing was employed to investigate the molecular mechanisms, particularly focusing on the PINK1/Parkin-mediated mitophagy pathway. RESULTS: CA-TPP significantly reduced the required treatment dose of CA by 75%, maintaining its anticancer activity. In DU145 cells, CA-TPP induced cell death through the mitochondrial apoptosis pathway. RNA sequencing revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy via PINK1 shRNA alleviated the cytotoxic effects of CA-TPP, confirming the role of mitophagy in its mechanism. Additionally, CA-TPP treatment resulted in elevated ROS production, leading to mitochondrial apoptosis and mitophagy. CONCLUSIONS: The CA-TPP prodrug strategy enhances the specificity and anti-tumor effects of corosolic acid, offering a promising approach for targeted cancer therapy. This work opens new possibilities for mitochondria-targeted cancer treatments with reduced drug dosages. This study did not involve clinical trials, and thus trial registration is not applicable.