A Benzenesulfonamide-Based Mitochondrial Uncoupler Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOC metastasizes in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-depr...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular cancer therapeutics Vol. 20; no. 12; pp. 2398 - 2409
Main Authors:	Bi, Fangfang, Jiang, Ziyan, Park, Wonmin, Hartwich, Tobias M P, Ge, Zhiping, Chong, Kay Y, Yang, Kevin, Morrison, Madeline J, Kim, Dongin, Kim, Jaeyeon, Zhang, Wen, Kril, Liliia M, Watt, David S, Liu, Chunming, Yang-Hartwich, Yang
Format:	Journal Article
Language:	English
Published:	United States 01-12-2021
Subjects:	Animals Apoptosis Benzenesulfonamides Carbonic Anhydrase Inhibitors - pharmacology Carbonic Anhydrase Inhibitors - therapeutic use Carcinoma, Ovarian Epithelial - drug therapy Cell Line, Tumor Endoplasmic Reticulum Stress - drug effects Female Humans Immunogenic Cell Death - drug effects Mice Mice, Nude Sulfonamides - pharmacology Sulfonamides - therapeutic use
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOC metastasizes in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro- -(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells Y3 was well tolerated and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect patients with ovarian cancer against relapse.
Bibliography:	Authors’ contributions F.B, Z.J., W.P., and T.H. carried out the experiments, analyzed the data, and contributed to the manuscript preparation. Z.G., K.C, K.Y., M.M., W.Z., and L.K. carried out the experiments. D.K. and J.K. provided experimental materials and contributed to the manuscript preparation. C.L. and D.W. provided the compounds and contributed to the manuscript preparation. Y.Y. conceived and designed the experiments and prepared the manuscript. All authors discussed the results and commented on the manuscript.
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.MCT-21-0396