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

被引：116

作者：

Chefetz, Ilana ^{[1
,19
]}

Grimley, Edward ^{[16
,17
,20
]}

Yang, Kun ^{[1
]}

Hong, Linda ^{[2
,20
]}

Vinogradova, Ekaterina V. ^{[3
]}

Suciu, Radu ^{[3
]}

Kovalenko, Ilya ^{[4
]}

Karnak, David ^{[5
]}

Morgan, Cynthia A. ^{[6
]}

Chtcherbinine, Mikhail ^{[6
]}

Buchman, Cameron ^{[6
]}

Huddle, Brandt ^{[7
]}

Barraza, Scott ^{[7
]}

Morgan, Meredith ^{[5
]}

Bernstein, Kara A. ^{[8
]}

Yoon, Euisik ^{[9
]}

Lombard, David B. ^{[10
,11
]}

Bild, Andrea ^{[12
]}

Mehta, Geeta ^{[13
]}

Romero, Iris ^{[14
]}

Chiang, Chun-Yi ^{[14
]}

Landen, Charles ^{[15
]}

Cravatt, Benjamin ^{[3
]}

Hurley, Thomas D. ^{[6
]}

Larsen, Scott D. ^{[7
]}

Buckanovich, Ronald J. ^{[1
,2
,16
,17
,18
]}

机构：

[1] Univ Michigan, Div Hematol Oncol, Dept Internal Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA

[3] Scripps Res Inst, Dept Mol Med, La Jolla, CA USA

[4] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[6] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[7] Univ Michigan, Coll Pharm, Vahlteich Med Chem Core, 428 Church St, Ann Arbor, MI 48109 USA

[8] Univ Pittsburgh, UPMC Hillman Canc Ctr, Dept Microbiol & Mol Genet, Pittsburgh, PA USA

[9] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[11] Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA

[12] Univ Utah, Dept Pharmacol & Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA

[13] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA

[14] Univ Chicago, Dept Obstet & Gynecol, Sect Gynecol Oncol, Chicago, IL 60637 USA

[15] Univ Virginia, Sch Med, Dept Obstet & Gynecol, Charlottesville, VA 22908 USA

[16] Univ Pittsburgh, Div Hematol Oncol, Dept Internal Med, Div Gynecol Oncol,Dept Obstet & Gynecol, Pittsburgh, PA 15260 USA

[17] Univ Pittsburgh, UPMC Hillman Canc Ctr, Pittsburgh, PA 15260 USA

[18] Magee Womens Res Inst, Pittsburgh, PA 15213 USA

[19] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[20] Loma Linda Univ, Med Ctr, Loma Linda, CA USA

来源：

CELL REPORTS | 2019年 / 26卷 / 11期

关键词：

ALDEHYDE DEHYDROGENASE; BREAST-CANCER; DISULFIRAM; CHEMORESISTANCE; PHARMACOLOGY; CHEMOTHERAPY; METABOLISM; RESISTANCE; MECHANISM; IDENTIFY;

D O I：

10.1016/j.celrep.2019.02.032

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer "sternness," 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.

引用

页码：3061 / +

页数：21

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