Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors

Background There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of ovarian research Vol. 17; no. 1; pp. 226 - 17
Main Authors:	Udumula, Mary P, Rashid, Faraz, Singh, Harshit, Pardee, Tim, Luther, Sanjeev, Bhardwaj, Tanya, Anjaly, Km, Piloni, Sofia, Hijaz, Miriana, Gogoi, Radhika, Philip, Philip A, Munkarah, Adnan R, Giri, Shailendra, Rattan, Ramandeep
Format:	Journal Article
Language:	English
Published:	BioMed Central Ltd 14-11-2024 BMC
Subjects:	Amino acids Apoptosis Cancer Chemotherapy CPI-613 Cytochrome c Development and progression Ethylenediaminetetraacetic acid Metabolites Mitochondria Ovarian cancer Scientific equipment and supplies industry Superoxide United States California
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Background There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. Methods Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. Results Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Conclusion Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors. Keywords: Ovarian cancer, CPI-613, Mitochondria, Apoptosis
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1757-2215 1757-2215
DOI:	10.1186/s13048-024-01546-6