Visomitin as a differentiation-inducing therapeutic agent through SYK inhibition in AML.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the rapid proliferation of immature myeloblasts and resistance to apoptosis. Overcoming the differentiation block and apoptotic resistance remains a major challenge in AML therapy. Visomitin, a mitochondria-targeted antioxidant, has shown protective effects in other contexts, but its potential in AML has not been explored. METHODS: We examined the effects of Visomitin on AML cell differentiation and apoptosis using flowcytometry, including CD11b, CD14 staining and ROS measurement. Western blot analysis of Bcl-2 family proteins and p21/p16/Rb axis. Potential underlying mechanisms were explored through SYK activation. Additionally, primary AML patient samples were tested to assess translational relevance, and in vivo efficacy was evaluated in a xenograft mouse model. RESULTS: Treatment with Visomitin promoted differentiation of AML cells, as indicated by increased CD14 expression, and induced apoptosis by downregulating anti-apoptotic proteins (Mcl-1, Bcl-XL) while upregulating pro-apoptotic factors (Bak, Bax). Mechanistic studies suggested that Visomitin-induced ROS accumulation enhances AML differentiation and apoptosis. Notably, Visomitin selectively increased ROS in AML cells while reducing ROS levels in normal myeloid cells. Pharmacological and genetic rescue experiments further imply that Visomitin's anti-AML effects are mediated by ROS-dependent inhibition of SYK. In vivo, Visomitin suppressed tumor growth and elevated ROS within tumors. Furthermore, ex vivo treatment of primary AML cells reduced proliferation, highlighting potential clinical applicability. CONCLUSION: These findings suggest that Visomitin exerts potent anti-leukemic effects by simultaneously promoting differentiation and apoptosis through ROS-mediated SYK inhibition. The selective activity against malignant cells and favorable in vivo efficacy suggest that Visomitin is a potential therapeutic agent for AML.