A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

Ilana Chefetz; Edward Grimley; Kun Yang; Linda Hong; Ekaterina V. Vinogradova; Radu Suciu; Ilya Kovalenko; David Karnak; Cynthia A. Morgan; Mikhail Chtcherbinine; Cameron Buchman; Brandt Huddle; Scott Barraza; Meredith Morgan; Kara A. Bernstein; Euisik Yoon; David B. Lombard; Andrea Bild; Geeta Mehta; Iris Romero; Chun-Yi Chiang; Charles Landen; Benjamin Cravatt; Thomas D. Hurley; Scott D. Larsen; Ronald J. Buckanovich

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

2019

Summary: 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. : Chefetz et al. identify ALDH1A enzyme family inhibitors (ALDH1Ai) that trigger necroptosis in CD133+ ovarian CSCs. Necroptosis is mediated in part by the induction of mitochondrial uncoupling proteins and reduction of oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation and growth and increasing tumor eradication rates. Keywords: ALDH, CSC, necroptosis, CD133+, cell death, ovarian cancer, resistance

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