| Literature DB >> 30865894 |
Ilana Chefetz1, Edward Grimley2, Kun Yang1, Linda Hong3, Ekaterina V Vinogradova4, Radu Suciu4, Ilya Kovalenko5, David Karnak6, Cynthia A Morgan7, Mikhail Chtcherbinine7, Cameron Buchman7, Brandt Huddle8, Scott Barraza8, Meredith Morgan6, Kara A Bernstein9, Euisik Yoon10, David B Lombard11, Andrea Bild12, Geeta Mehta13, Iris Romero14, Chun-Yi Chiang14, Charles Landen15, Benjamin Cravatt4, Thomas D Hurley7, Scott D Larsen8, Ronald J Buckanovich16.
Abstract
Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer "stemness," and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133+ ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.Entities:
Keywords: ALDH; CD133(+); CSC; cell death; necroptosis; ovarian cancer; resistance
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Year: 2019 PMID： 30865894 PMCID： PMC7061440 DOI： 10.1016/j.celrep.2019.02.032
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423