Mitochondria as Target for Tumor Management of Hemangioendothelioma

Aims: Hemangioendothelioma (HE) may be benign or malignant. EOMA cells are validated to study mechanisms in HE. This work demonstrates that EOMA cells heavily rely on mitochondria to thrive. Thus, a combination therapy including weak X-ray therapy (XRT, 0.5Gy) and a standardized natural berry extract (NBE) that is known to be effective in managing experimental HE and has been awarded with Food and Drug Administration - Investigational New Drug Application (FDA-IND # 140318) for studies on infantile hemangioma was tested. Results: NBE treatment alone selectively attenuated basal oxygen consumption rate (OCR) of EOMA cells. NBE significantly sensitized EOMA, but not MAE, cells to XRT-dependent attenuation of mitochondrial respiration and ATP production. Combination treatment selectively and potently influenced mitochondrial dynamics in EOMA cells such that fission was augmented. Markers of mitochondrial fission were induced by the said combination therapy. This was achieved by lowering of mitochondrial Sirtuin 3 (SIRT3) causing increased phosphorylation of AMP-activated protein kinase (AMPK). A key role of SIRT3 in loss of EOMA cell viability caused by the combination therapy was evident when pyrroloquinoline quinone, an inducer of SIRT3, pre-treatment rescued these cells. Innovation and Conclusion: Mitochondria-targeting NBE significantly extended survival of HE-affected mice. The beneficial effect of combination therapy was, however, far more potent with 3-fold increase in murine survival. Mitochondria-targeted antitumor therapies warrant further consideration.