A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers

Simple Summary Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes involved in the synthesis of retinoic acid, which is necessary for the normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. ALDH1A3, one of the enzymes that belong to the ALD1A subfamily, is also expressed at high levels in many human cancers like glioblastoma and mesothelioma. Herein, we review the role of ALDH1A3 in cancer, showing its relation with excessive proliferation, chemoresistance, and invasiveness. We also illustrate the current attempts to develop ALDH1A3-selective inhibitors and specific fluorescent probes that are potentially useful for cancer therapy and fluorescence-guided tumor resection.Abstract Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.