1. Development of New Platinum-Based Anticancer Agents Targeting Ovarian Cancer Stem Cells
- Author
-
Stilgenbauer, Morgan Grasselli
- Subjects
- Biochemistry, Chemistry, Inorganic Chemistry, Ovarian Cancer, Cancer Stem Cells, Platinum, Prodrugs, CD36, Mitochondrial-targeting, DNA Nanosprings
- Abstract
A foremost problem in ovarian cancer therapy is that conventional platinum-based metallodrugs promote cancer relapse via enriching cancer stem cells (CSCs). In this study, we present the first platinum-based anticancer agent that can target and eliminate ovarian CSCs. CD36, the protein responsible for fatty acid uptake, is upregulated in ovarian cancer tumors and site of metastasis due to the available fatty acids in the omentum. Oxidative phosphorylation in mitochondria has been recognized as the preferred energy production process in ovarian CSCs. Therefore, we synthesized fatty acid-like cationic lipophilic Pt(IV) prodrugs to target CD36-dependent uptake and mitochondria toward eradicating ovarian CSCs. First, CD36-dependent uptake was, and biological studies were completed to confirm the prodrug’s effect on ovarian CSCs compared to cisplatin. To examine drug efficacy, cytotoxicity profiles were evaluated, and mitochondrial platinum uptake and fluorescent imaging were conducted to confirm mitochondrial localization of a Pt(IV) prodrug labelled with rhodamine. Flow cytometric analysis was utilized to assess mitochondrial damage by production of superoxide and loss of mitochondrial membrane potential. Upon confirming mitochondrial damage, ovarian CSCs were treated showing the ability of the prodrug to eradicate CSCs. In vivo efficacy was measured using a SKOV3 xenograft model. Another characteristic of CSCs is the increased capacity for metastasis, which is made up of motility and invasion. By controlling migration of cells, metastatic disease can be prevented. DNA nanosprings that respond to change in pH have been developed, and here, biological imaging studies to test for the phenotype of increased migration has been evaluated. By successfully eliminating CSCs and controlling migration, these treatments serve as an effective method to target these populations responsible for a worse patient outcome. Treatment with these agents could have future potential in eliminating chemoresistance and relapse in ovarian cancer.
- Published
- 2020