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Researchers Explore New Strategy for Overcoming Cisplatin Resistance in Metastatic Prostate Cancer

By: Amy MacDonald, MS
Posted: Tuesday, August 22, 2023

It is known that malignant transformation in prostate cancer involves the metabolic switching of cancer cells from glycolysis to efficient fatty acid oxidation. This metabolic rewiring is controlled by the androgen receptor (AR). Although the use of AR antagonists may extend survival in some patients with prostate cancer, for others, they are ineffective. In addition, metastatic prostate cancer, unlike many other cancers, is typically resistant to treatment with more conventional cisplatin-based chemotherapy.

Shanta Dhar, PhD, of the University of Miami Miller School of Medicine, and colleagues sought to combine these observations about the properties of prostate cancer cells and to use them to develop proposed mechanisms for cisplatin resistance. Published in the American Chemical Society’s journal ACS Central Science, their research revealed that the cisplatin prodrug Platin-L may inhibit the fatty acid oxidation of prostate cancer cells by interacting with the enzyme CPT1A, which is essential for fatty acid oxidation.

“We hypothesized that inhibition of fatty acid oxidation in the prostate cancer microenvironment may be a promising strategy to sensitize these otherwise-resistant cells toward chemotherapy,” the researchers stated.

The researchers conducted extensive in vitro and murine experiments to test their hypotheses. They employed a pool of patient biopsies from 21 new patients and 17 androgen deprivation therapy–treated patients to understand the levels of CPT1A in the benign and cancerous regions of prostate tissue. Additionally, they studied the metabolic profile of several prostate cancer cell lines, including cisplatin-sensitive and cisplatin-resistant lines. Finally, they incorporated Platin-L into an orally administrable prostate-specific membrane antigen–targeted biodegradable nanoparticle to test their hypothesis about the interaction between Platin-L and CPT1A in mice. The authors concluded that cisplatin prodrug activity may be clinically relevant, since Platin-L–loaded orally administered nanoparticles were found to be effective at reducing prostate cancer tumor volume in cisplatin-resistant tumor models.

Disclosure: The study authors reported no conflicts of interest.

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