The potential value of amlexanox in the treatment of cancer: molecular targets and therapeutic perspectives

Biochem Pharmacol. 2021 Dec 27:114895. doi: 10.1016/j.bcp.2021.114895. Online ahead of print.ABSTRACTAmlexanox (AMX) is an azoxanthone drug used for decades for the treatment of mouth aphthous ulcers and now considered for the treatment of diabetes and obesity. The drug is usually viewed as a dual inhibitor of the non-canonical IκB kinases IKK-ɛ (inhibitor-kappaB kinase epsilon) and TBK1 (TANK-binding kinase 1). But a detailed target profile analysis indicated that AMX binds directly to twelve protein targets, including different enzymes (IKK-ɛ, TBK1, GRK1, GRK5, PDE4B, 5- and 12-lipoxygenases) and non-enzyme proteins (FGF-1, HSP90, S100A4, S100A12, S100A13). AMX has been demonstrated to have marked anticancer effects in multiple models of xenografted tumors in mice, including breast, colon, lung and gastric cancers and in onco-hematological models. The anticancer potency is generally modest but largely enhanced upon combination with cytotoxic (temozolide, docetaxel), targeted (selumetinib) or biotherapeutic agents (anti-PD-1 and anti-CTLA4 antibodies). The multiple targets participate in the anticancer effects, chiefly IKK-ɛ/TBK1 but also S100A proteins and PDE4B. The review presents the molecular basis of the antitumor effects of AMX. The capacity of the drug to block nonsense-mediated mRNA decay (NMD) is also discussed, as well as AMX-induced reduction of cancer-related pain. Altogether, the analysis provides a survey of the anticancer action of AMX, with the implicate...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research