Ambroxol induces myeloma cell death by inhibiting autophagy

In the last decade, newly developed drugs have significantly improved the prognosis of patients with multiple myeloma (MM). However, most patients relapse sooner or later, and thus MM remains an incurable hematological malignancy. In addition, serious adverse events occasionally hamper the continuation of treatment. Exploitation of new drugs that potentiate antitumor activities and alleviate the adverse effects of existing drugs is needed. Here, we found through drug repositioning that ambroxol hydrochloride (ambroxol) induces apoptosis of MM cells. Interestingly, turnover and reporter assays revealed that ambroxol inhibits the late stage of autophagy. Transmission electron microscopy observation also revealed that MM cells treated with ambroxol accumulated autophagic vacuoles in the cytoplasm, further supporting the inhibition of late-stage autophagy. Existing anti-MM drugs demonstrate various effects on autophagy; panobinostat, a histone deacetylase inhibitor, induces autophagy, whereas bortezomib and lenalidomide do not. When administered together, ambroxol and panobinostat exhibited a synergistic antimyeloma effect, likely due to ambroxol inhibiting the activation of panobinostat-induced autophagy while downregulating MCL-1 expression. In the KMS11 xenograft model, ambroxol significantly delayed tumor growth when administered alone; when co-administered with panobinostat, ambroxol synergistically enhanced the panobinostat-induced inhibition of tumor growth. Interestingly, concomitant use of ambroxol and panobinostat alleviated panobinostat-induced diarrhea. Gene set enrichment and pathway analyses also revealed that ambroxol increased the expression of genes related to autophagy inhibition and unfolded protein response. These results suggested that autophagy is a promising therapeutic target for MM.