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Ibrahim et al ALDHs and prostate cancer

Figure 2: Cytochrome P450 (CYP) activation of cyclophosphamide (CPA). Initial hydroxylation of CPA in the liver by CYP isoforms
leads to generation of aldophosphamide, an intermediate which is a substrate for aldehyde dehydrogenases (ALDHs) metabolism. If
aldophosphamide enters circulation it is very likely to be detoxified in ALDH-expressing cells including cancer stem cells (CSCs), but not in
cancer cells with low or absent ALDH expression

ALDH inhibitor DEAB significantly reduced cellular significantly higher levels of the stemness markers
proliferation in vitro. This investigation suggested that Nanog, HIF-1α, Notch1, CD44 and ALDH.
two subtypes of MGSCs, harbouring distinct metabolic
signaling pathways, constitute intratumoural glioma The latter study provides an alternative route for
heterogeneity. ALDH1A3 was proposed to play an therapeutic intervention, focussed on reprogramming
important role in the glycolysis pathway, via catalytic glycolytic pathways. ALDHs such as the 1A3 isoform
metabolism of acetaldehyde to acetate that is in turn could be a key player in such therapeutic intervention.
linked to the tricarboxylic acid (TCA) cycle [220] . The However, as we [45] and others [46,87,222] have discussed
glycolysis pathway is interesting because of the link to previously, the expression of ALDHs in normal
the TME and what is defined as the “Warburg effect”. tissue expression remain a stumbling block towards
A recent study [221] reported on the mitochondrial a credible clinical therapy. However, advances in
pyruvate carrier 1 (MPC1) gene in knockout studies drug delivery technologies could in the future enable
using CRISPR/Cas9 technology in RM-1 murine PCa administration of an ALDH inhibitor, which is potently
cells. The MPC1 gene knockout cells revealed a selective for a specific isoform. For example, a recent
metabolism reprogramming to aerobic glycolysis with report [223] indicate that the latter might be achieved
reduced ATP production, increase in cell migration in combination with radiotherapy, or as an option to
and resistance to both chemo- and radiotherapy. sensitise heterogeneous prostate tumour responses
In addition, the MPC1 knockout cells expressed to docetaxel.

Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ Aug 21, 2018 9