Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model
Abstract
<jats:p>Disease recurrence is the major cause of morbidity and mortality of ovarian
cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy,
PARP inhibitors significantly improve the overall survival of patients with BRCA mutations
but is of little benefit to patients without homologous recombination deficiency (HRD).
The stem-like tumor-initiating cell (TIC) population within OC tumors are thought
to contribute to disease recurrence and chemoresistance. Therefore, there is a need
to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing
analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes
involved in drug metabolism, oxidative phosphorylation and reactive oxygen species
(ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that
showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs
were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone
methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on
viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared
to adherent cells. The compounds promoted ROS accumulation and oxidative stress and
disulfiram, elesclomol and salinomycin increased cell death following carboplatin
treatment compared to carboplatin alone. Disulfiram and salinomycin were effective
in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that
enhancing oxidative stress in TICs can prevent OC recurrence.</jats:p>
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https://hdl.handle.net/10161/26241Published Version (Please cite this version)
10.3390/cancers12061645Publication Info
Harrington, Brittney S; Ozaki, Michelle K; Caminear, Michael W; Hernandez, Lidia F;
Jordan, Elizabeth; Kalinowski, Nicholas J; ... Annunziata, Christina M (n.d.). Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy
Ovarian Cancer Relapse Model. Cancers, 12(6). pp. 1645-1645. 10.3390/cancers12061645. Retrieved from https://hdl.handle.net/10161/26241.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Michael Caminear
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