Therapeutic Efficacy of Pharmacological Ascorbate on Braf Inhibitor Resistant Melanoma Cells In Vitro and In Vivo

Cells

Sarah Plöger¹  Francisco Meraz-Torres¹  Matti Böcker¹  Tobias Sinnberg¹  Constanze Hirn¹  Ulrich M. Lauer²  Christian Leischner³  Heike Niessner³  Sascha Venturelli³  Olga Renner³  Markus Burkard³  Christian Busch⁴ 

[1] Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany;Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany;Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany;Dermatologie zum Delfin, Stadthausstrasse 12, 8400 Winterthur, Switzerland;

关键词: malignant melanoma;    cancer;    ascorbate;    vitamin C;    BRAF inhibitor;    BRAF^V600E;   

DOI  :  10.3390/cells11071229

来源: DOAJ

【 摘 要 】

High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach to treating refractory melanomas, e.g., with secondary resistance to targeted BRAF inhibitor therapy. BRAF mutated melanoma cells were treated with ascorbate alone or in combination with the BRAF inhibitor vemurafenib. Viability, cell cycle, ROS production, and the protein levels of phospho-ERK1/2, GLUT-1 and HIF-1α were analyzed. To investigate the treatment in vivo, C57BL/6NCrl mice were subcutaneously injected with D4M.3A (Braf^V600E) melanoma cells and treated with intraperitoneal injections of ascorbate with or without vemurafenib. BRAF mutated melanoma cell lines either sensitive or resistant to vemurafenib were susceptible to the induction of cell death by pharmacological ascorbate. Treatment of Braf^V600E melanoma bearing mice with ascorbate resulted in plasma levels in the pharmacologically active range and significantly improved the therapeutic effect of vemurafenib. We conclude that intravenous high-dose ascorbate will be beneficial for melanoma patients by interfering with the tumor’s energy metabolism and can be safely combined with standard melanoma therapies such as BRAF inhibitors without pharmacological interference.

【 授权许可】

Unknown