Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling

Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy. Leukemia: A new combination to kill cancer cells A mutated form of the bacterial protein pneumolysin offers a new approach to treating acute myeloid leukemia (AML), due to its ability to stimulate cancer cells to undergo a form of cell suicide called apoptosis. Researchers in China led by Xuemei Zhang at Chongquing Medical University studied the effects of a pneumolysin derivative on cultured human and mouse AML cells. They identified the mechanism by which this derivative activates a known molecular signaling system to inhibit the process of autophagy, in which cells routinely ‘clean up’ degraded or unnecessary components during normal maintenance. This inhibition of autophagy then induced the apoptosis that killed cancer cells. The effect became more pronounced when the pneumolysin derivative was combined with the existing autophagy-inhibiting drug chloroquine. The new combination could be safer and more effective than using chloroquine alone.