A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719302037 |
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doaj-21d10f5934934f7c8c9e8ddf07b5d168 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Cell Reports |
| author_facet |
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 |
| author_sort |
Ilana Chefetz |
| title |
A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells |
| title_short |
A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells |
| title_full |
A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells |
| title_fullStr |
A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells |
| title_full_unstemmed |
A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells |
| title_sort |
pan-aldh1a inhibitor induces necroptosis in ovarian cancer stem-like cells |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2019-03-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124719302037 |
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doaj-21d10f5934934f7c8c9e8ddf07b5d1682020-11-25T00:59:08ZengElsevierCell Reports2211-12472019-03-01261130613075.e6A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like CellsIlana Chefetz0Edward Grimley1Kun Yang2Linda Hong3Ekaterina V. Vinogradova4Radu Suciu5Ilya Kovalenko6David Karnak7Cynthia A. Morgan8Mikhail Chtcherbinine9Cameron Buchman10Brandt Huddle11Scott Barraza12Meredith Morgan13Kara A. Bernstein14Euisik Yoon15David B. Lombard16Andrea Bild17Geeta Mehta18Iris Romero19Chun-Yi Chiang20Charles Landen21Benjamin Cravatt22Thomas D. Hurley23Scott D. Larsen24Ronald J. Buckanovich25Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USADivision 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, USADivision of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USADivision of Gynecology-Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USADepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USADepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USADepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USAVahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USAVahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USADepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USADepartment of Microbiology and Molecular Genetics, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USADepartment of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USADepartment of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI, USADepartment of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USADepartment of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USADepartment of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USADepartment of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USADepartment of Obstetrics and Gynecology, School of Medicine, University of Virginia, Charlottesville, VA, USADepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USAVahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USADivision 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 authorSummary: 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, resistancehttp://www.sciencedirect.com/science/article/pii/S2211124719302037 |