Targeting of mitochondrial fission through natural flavonones elicits anti-myeloma activity

Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in cancer pathobiology, making mitochondria-targeting therapies a promising avenue for the treatment of several cancers, including multiple myeloma (MM). Flavonones are natural flavonoids endowed with mitochondrial-targeting activities. Herein, we investigated the capability of two flavonones, Hesperetin (Hes) and Naringenin (Nar), to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcription activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hes and Nar, was capable to recapitulate the phenotypic and molecular perturbations of each flavonone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, induce apoptosis and rewire the metabolism of MM cells via the targeting of the mitochondrial fission pathway.