Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model.

Autor: Harrington BS; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Ozaki MK; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Caminear MW; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Hernandez LF; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Jordan E; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Kalinowski NJ; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Goldlust IS; The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA., Guha R; The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA., Ferrer M; The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA., Thomas C; The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA., Shetty J; CCR Sequencing Facility, Leidos Biomedical Research, Inc., FNLCR, Frederick, MD 21701 , USA., Tran B; CCR Sequencing Facility, Leidos Biomedical Research, Inc., FNLCR, Frederick, MD 21701 , USA., Wong N; CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., House CD; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Annunziata CM; Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2020 Jun 21; Vol. 12 (6). Date of Electronic Publication: 2020 Jun 21.
DOI: 10.3390/cancers12061645
Abstrakt: 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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