Lipid Metabolism\nModulatory Cisplatin Prodrug Sensitizes\nResistant Prostate Cancer toward Androgen Deprivation Therapy

Mainstream treatment modalities which dominate the therapeutic\nlandscape of prostate cancer (PCa) are prostatectomy, radiation therapy,\nand androgen deprivation therapy (ADT) or castration. These therapeutic\noptions can extend the life expectancy of the patients but eventually\nfail to completely cure the disease. Despite undergoing ADT, patients\nstill experience disease recurrence. One of the reasons for this recurrence\nis the binding of the basal androgens present in blood plasma to the\nandrogen receptor (AR). At this stage, the disease becomes castration-resistant\nprostate cancer (CRPC) showing resistance to ADT promoting progression,\nand there is no effective treatment available. Although another male\ncancer such as testicular cancer responds to cisplatin-based therapy\nvery well, PCa is resistant to cisplatin. In our continued effort\nto find the pathways that are important for such resistance, we link\nin this report, tumor metabolism driven androgen regulation and PCa\nresistance toward cisplatin-based therapy. To delve deeper into understanding\nhow metabolic modulatory cisplatin prodrugs can be used to target\nthe ADT resistant population, we demonstrate that metabolic inhibition\nby a cisplatin prodrug, Platin-L has the potential to modulate AR\nactivity and resensitize ADT resistant cells toward cisplatin-based\nchemotherapy as well as ADT. The mode of action for Platin-L is inhibition\nof fatty acid oxidation (FAO) of prostate cancer cells. We demonstrated\nthat FAO inhibition by Platin-L in PCa cells contribute to AR regulation\nresulting in altered tumorigenicity of androgen sensitive prostate\ncancer.