New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance

Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate (PCa) is an example that resistant one the most potent chemotherapeutics, cisplatin. PCa survive and proliferate using fatty acid oxidation (FAO), dependence on fat utilization increases as disease progresses toward a form. Using pool patient biopsies, we validated expression key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for metabolism. We then discovered cisplatin prodrug, Platin-L, can inhibit FAO by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, documented presence available carboxylic group near long chain linker Pt(IV) center crucial CPT1A binding. As result metabolism disruption transition adaptive glucose-dependent chemosensitive state. Potential clinical translation Platin-L will require delivery vehicle direct it prostate tumor microenvironment. Thus, incorporated in biodegradable tumor-targeted orally administrable nanoformulation demonstrated its safety efficacy. The distinctive inhibitory property be potential relevance offers use otherwise cancer.