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

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

Author information

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

PMID:
30865894
DOI:
10.1016/j.celrep.2019.02.032
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