前药
顺铂
前列腺癌
癌症研究
肉碱
肿瘤微环境
连接器
化学
β氧化
癌症
新陈代谢
药理学
癌细胞
酶
生物化学
医学
内科学
化疗
肿瘤细胞
计算机科学
操作系统
作者
Akil A. Kalathil,Subham Guin,Akash Ashokan,Uttara Basu,Bapurao Surnar,Katiana S. Delma,Leonor M. Lima,Oleksandr N. Kryvenko,Shanta Dhar
出处
期刊:ACS central science
[American Chemical Society]
日期:2023-07-12
卷期号:9 (7): 1297-1312
被引量:10
标识
DOI:10.1021/acscentsci.3c00286
摘要
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.
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