Mitochondria as Target for Tumor Management of Hemangioendothelioma

Abstract

Aims: Hemangioendothelioma (HE) may be benign or malignant. Mouse hemangioendothelioma endothelial (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, 0.5 Gy) and a standardized natural berry extract (NBE) was tested. This NBE is known to be effective in managing experimental HE and has been awarded with the Food and Drug Administration Investigational New Drug (FDA-IND) number 140318 for clinical studies on infantile hemangioma. Results: NBE treatment alone selectively attenuated basal oxygen consumption rate of EOMA cells. NBE specifically sensitized EOMA, but not murine aortic endothelial cells to XRT-dependent attenuation of mitochondrial respiration and adenosine triphosphate (ATP) production. Combination treatment, selectively and potently, influenced mitochondrial dynamics in EOMA cells such that fission was augmented. 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, pretreatment rescued these cells. Innovation and Conclusion: Mitochondria-targeting NBE significantly extended survival of HE-affected mice. The beneficial effect of NBE in combination with weak X-ray therapy was, however, far more potent with threefold increase in murine survival. The observation that safe natural products may target tumor cell mitochondria and sharply lower radiation dosage required for tumor management warrants clinical testing. Antioxid. Redox Signal. 34,[137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153]

Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells

“…Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR) measurements were performed using a Seahorse Bioscience XF-96 instrument as described previously (64,65). On the day prior to the experiment, the sensor cartridge was hydrated overnight using the calibration buffer supplied by the manufacturer (Agilent, Santa Clara, CA).…”

The Role of Natural Extracts in the Management of Infantile Hemangiomas and Vascular Tumors

“…Natural berry extract (NBE) was awarded Food and Drug Administration—Investigational New Drug (FDA–IND; 140318) for human testing against infantile hemangioma. 12 It was also demonstrated that a standardized anthocyanin-rich NBE was effective in prolonging survival of hemangioendothelioma bearing mice. 13 …”

“…In any case, the cumulated adverse side effects of radiation and chemotherapy raise serious concerns for the quality of life of the surviving patient. 12 …”

“… 11 Besides hemangiomas, which are definitely benign tumors despite their overgrowth potential, there are other vascular tumors like hemangioendotheliomas (HE), which may display intermediate characteristics between benign hemangiomas and highly malignant angiosarcomas. 12 Some malignant tumors, including vascular ones, have benefited over time from radiotherapy, but when it comes to children, the therapeutic doses must be drastically reduced in order not to cause more harm than good. Lower doses of radiation combined with conventional chemotherapy may be used, but chemotherapeutic drugs are also highly cytotoxic both for tumor cells but also for healthy cells in the child.…”

“…In this context, the association of chemotherapy or ionizing radiation therapy with the administration of dietary active substances from natural sources can be of real benefit in the treatment of vascular cancers in children. 12 , 13 …”