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.

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 / antagonists & inhibitors*
  • Aldehyde Dehydrogenase 1 / 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
  • Aldehyde Dehydrogenase 1
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Aldh1 protein, mouse
  • Retinal Dehydrogenase