Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) (ALDH1A1/ALDH1A3)

Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and A3 (ALDH1A3) are cytosolic enzymes that catalyze the NAD(P)+-dependent oxidation of aldehydes to carboxylic acids and the conversion of retinaldehyde to retinoic acid (Duester, 2008, PMID: 18774151). In many malignancies, high expression and activity of these isoforms (the ALDHhigh phenotype) serve as a functional marker for cancer stem cells (CSCs), which are responsible for tumor initiation, metastasis, and recurrence (Tomita et al., 2016, PMID: 26823732). These enzymes protect CSCs by detoxifying exogenous chemotherapeutic agents like cyclophosphamide and endogenous reactive oxygen species (ROS) generated during therapy (Marcato et al., 2011, PMID: 21430067). ALDH1A3 has specifically been linked to the mesenchymal subtype of glioblastoma and aggressive breast cancer phenotypes (Chen et al., 2015, PMID: 25561511). Therapeutic strategies targeting these enzymes involve small-molecule inhibitors such as NCT-501 or repurposed drugs like Disulfiram, which aim to deplete the CSC pool and sensitize tumors to standard-of-care treatments (Yang et al., 2015, PMID: 26154444; Liu et al., 2012, PMID: 22470163). However, challenges remain regarding the potential toxicity to normal stem cell populations and the need for isoform-specific inhibition to avoid off-target effects on ALDH2 (Levi et al., 2009, PMID: 19252490).

Other names

ALDH1A1ALDH1A3Retinaldehyde dehydrogenase 1Retinaldehyde dehydrogenase 3RALDH1RALDH3Aldehyde dehydrogenase 1

Inhibition of ALDH1A1 and ALDH1A3 enzyme activity to increase intracellular toxic aldehydes and reactive oxygen species while depleting retinoic acid, leading to cancer stem cell apoptosis and sensitization to chemotherapy.