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
Affiliations
Ilana Chefetz
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Edward Grimley
Division of Hematology-Oncology, Department of Internal Medicine, Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
Kun Yang
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Linda Hong
Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
Ekaterina V. Vinogradova
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
Radu Suciu
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
Ilya Kovalenko
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
David Karnak
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
Cynthia A. Morgan
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Mikhail Chtcherbinine
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Cameron Buchman
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Brandt Huddle
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Scott Barraza
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Meredith Morgan
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
Kara A. Bernstein
Department of Microbiology and Molecular Genetics, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
Euisik Yoon
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
David B. Lombard
Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA
Andrea Bild
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
Geeta Mehta
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
Iris Romero
Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA
Chun-Yi Chiang
Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA
Charles Landen
Department of Obstetrics and Gynecology, School of Medicine, University of Virginia, Charlottesville, VA, USA
Benjamin Cravatt
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
Thomas D. Hurley
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Scott D. Larsen
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
Ronald J. Buckanovich
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA; Division of Hematology-Oncology, Department of Internal Medicine, Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Magee-Womens Research Institute, Pittsburgh, PA, USA; Corresponding author
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
