Authors:

Sarah Batten

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About Paper:

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second-leading cause of cancer death among men in the United States, representing 24.3% of all new cancer cases in the U.S. Metastatic castration-resistant prostate cancer (mCRPC) is a lethal variant of prostate cancer that is associated with increased aggressiveness, cancer stemness, morbidity, and the risk of developing into taxane drug-resistant PCa. As taxanes are currently the first-line chemotherapeutic agents for mCRPC, there is a critical need to develop novel agents for the treatment of mCRPC. Clofazimine (CLF) is a potential immunomodulator drug that is FDA-approved for the treatment of leprosy. Recently, using a phenotype-based high-throughput drug screening, we demonstrated the in vitro (cell lines), in vivo (mouse xenograft models), and ex vivo (patient-derived primary tumor cells) efficacy of CLF in drug- resistant forms of chronic myeloid leukemia and multiple myeloma. In this study, we demonstrated that CLF is effective as a single agent and in combination with docetaxel (DTX) in a panel of PCa cell lines representing the diversity of CRPC patients. The response to CLF in the PCa cell lines was quantified using in vitro cytotoxicity assays, caspase 3/7 activity assay for apoptosis, cell cycle analysis, and aldehyde dehydrogenase activity assay for cancer stemness. Further, drug-induced changes were investigated using next-generation RNA sequencing analysis, where CLF treatment was found to modulate the expression of several non-coding RNAs that are associated with tumor cell proliferation, cell migration, and PCa drug resistance. Western Blotting was performed to validate the dysregulation of proteins associated with cell death and apoptosis, as well as the top dysregulated pathways in mCRPC following treatment with CLF. Our results support the preclinical development of CLF against aggressive forms of Prostate Cancer and provide additional insights into its mechanism of action.

Source:

Auburn University / Harrison College of Pharmacy / 2025

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Co-authors:

Sarah Batten