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

doi:10.1016/j.celrep.2019.02.032

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 RomeroChun-Yi Chiang, Charles Landen, Benjamin Cravatt, Thomas D Hurley, Scott D Larsen, Ronald J Buckanovich

Hormel Institute

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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.

Original language	English (US)
Pages (from-to)	3061-3075.e6
Journal	Cell reports
Volume	26
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2019.02.032
State	Published - Mar 12 2019

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Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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Chefetz, I., Grimley, E., Yang, K., Hong, L., Vinogradova, E. V., Suciu, R., Kovalenko, I., Karnak, D., Morgan, C. A., Chtcherbinine, M., Buchman, C., Huddle, B., Barraza, S., Morgan, M., Bernstein, K. A., Yoon, E., Lombard, D. B., Bild, A., Mehta, G., ... Buckanovich, R. J. (2019). A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells. Cell reports, 26(11), 3061-3075.e6. https://doi.org/10.1016/j.celrep.2019.02.032

Chefetz, I, Grimley, E, Yang, K, Hong, L, Vinogradova, EV, Suciu, R, Kovalenko, I, Karnak, D, Morgan, CA, Chtcherbinine, M, Buchman, C, Huddle, B, Barraza, S, Morgan, M, Bernstein, KA, Yoon, E, Lombard, DB, Bild, A, Mehta, G, Romero, I, Chiang, C-Y, Landen, C, Cravatt, B, Hurley, TD, Larsen, SD & Buckanovich, RJ 2019, 'A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells', Cell reports, vol. 26, no. 11, pp. 3061-3075.e6. https://doi.org/10.1016/j.celrep.2019.02.032

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AU - Suciu, Radu

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AU - Morgan, Cynthia A

AU - Chtcherbinine, Mikhail

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AU - Huddle, Brandt

AU - Barraza, Scott

AU - Morgan, Meredith

AU - Bernstein, Kara A

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AU - Lombard, David B

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AU - Mehta, Geeta

AU - Romero, Iris

AU - Chiang, Chun-Yi

AU - Landen, Charles

AU - Cravatt, Benjamin

AU - Hurley, Thomas D

AU - Larsen, Scott D

AU - Buckanovich, Ronald J

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

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

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