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

Cell Rep. 2019 Mar 12;26(11):3061-3075.e6. doi: 10.1016/j.celrep.2019.02.032.

Authors

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

Affiliations

¹ Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
² 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.
³ Division of Gynecology-Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
⁵ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Microbiology and Molecular Genetics, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁰ Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
¹³ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
¹⁵ Department of Obstetrics and Gynecology, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁶ 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. Electronic address: buckanovichrj@mwri.magee.edu.

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.

Keywords: ALDH; CD133(+); CSC; cell death; necroptosis; ovarian cancer; resistance.

Publication types

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

MeSH terms

AC133 Antigen / genetics
AC133 Antigen / metabolism
Aldehyde Dehydrogenase 1 Family / antagonists & inhibitors*
Aldehyde Dehydrogenase 1 Family / metabolism
Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm
Enzyme Inhibitors / pharmacology*
Female
Humans
Mice
Necroptosis*
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Ovarian Neoplasms / metabolism*
Oxidative Phosphorylation
Retinal Dehydrogenase / antagonists & inhibitors*
Retinal Dehydrogenase / metabolism

Substances

AC133 Antigen
Antineoplastic Agents
Enzyme Inhibitors
Aldehyde Dehydrogenase 1 Family
ALDH1A1 protein, mouse
Retinal Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding