New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance.
Akil A KalathilSubham GuinAkash AshokanUttara BasuBapurao SurnarKatiana S DelmaLeonor M LimaOleksandr N KryvenkoShanta DharPublished in: ACS central science (2023)
Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.
Keyphrases
- prostate cancer
- fatty acid
- cancer therapy
- induced apoptosis
- cell cycle arrest
- adipose tissue
- drug delivery
- oxidative stress
- radical prostatectomy
- endoplasmic reticulum stress
- cell death
- squamous cell carcinoma
- squamous cell
- binding protein
- blood pressure
- type diabetes
- metabolic syndrome
- case report
- climate change
- blood glucose
- weight loss
- human health
- long non coding rna
- pain management