A potential protective effect of 5-aminolevulinic acid against anticancer drug-induced damage to intestinal mucosa

An effective anti-cancer chemotherapy regimen can cause adverse events such as antineoplastic drug-induced oxidative stress in tissues. When hemeoxygenase-1 (HO1) is induced in tissues under oxidative stress, a tissue protective effect is observed. The non-proteinogenic amino acid 5-aminolevulinic acid (5-ALA) induces HO-1 in normal tissue and is hypothesized to provide an intestinal epithelial protective effect against drug-induced gastrointestinal mucosal disorders such as diarrhea and stomatitis. To validate this hypothesis, we introduced organoid culture from mouse intestinal epithelium. Using this organoid culture system, SN-38, the active metabolite of the antineoplastic drug irinotecan which is known to induce gastrointestinal mucosal disorders, was administered with and without 5-ALA to investigate the cytotoxic and protective effects of HO-1 suppression and expression. In normal intestinal epithelial cells, HO-1 induction by 5-ALA was observed. HO-1 expression was suppressed by the administration of SN-38 in the absence of 5-ALA, but was maintained by the co-administration of 5-ALA. In the mouse intestinal organoids, the same administration of 5-ALA induced HO-1 expression. When SN-38 was administered to the organoids, a cell death signal was expressed with an oxidative stress response, but the co-administration of 5-ALA induced HO-1 expression and cell death was decreased. The induction of HO-1 expression by 5-ALA administration suppresses intestinal epithelial cell death mediated by oxidative stress caused by antineoplastic drugs and is a potential new intestinal epithelial protective therapy against drug-induced gastrointestinal mucosal injury