Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition.
Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition.
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DOI：
10.1186/s12967-014-0247-5
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发表时间：
2014-09-03
影响因子：
7.4
通讯作者：
Guldberg P
中科院分区：
文献类型：
--
作者：
Abildgaard C;Dahl C;Basse AL;Ma T;Guldberg P
由于获得性耐药性的发展，通过靶向抑制致癌BRAF治疗黑色素瘤的进展有限。BRAFV 600 E参与黑色素瘤细胞的代谢重编程为共靶向代谢作为治疗方法提供了理论基础。我们研究了丙酮酸脱氢酶激酶抑制剂二氯乙酸（DCA）对人黑色素瘤细胞系生长和代谢活性的影响。在BRAFV 600 E突变的黑色素瘤细胞系中研究了DCA和BRAF抑制剂维罗非尼的联合作用。体外建立维罗非尼耐药细胞系，检测其对DCA的敏感性。DCA诱导糖酵解活性和细胞内ATP水平降低，并抑制细胞生长。用DCA和维罗非尼共处理BRAFV 600 E突变型黑色素瘤细胞比单独使用任一种化合物诱导细胞内ATP水平和细胞生长的降低更大。此外，对维罗非尼具有体外获得性耐药性的黑色素瘤细胞保留了其对DCA的敏感性。这些结果表明，DCA通过协同衰减能量产生来增强维罗非尼的作用。此外，在对维罗非尼具有获得性耐药性的黑色素瘤细胞中对DCA保持敏感性的证明可能对黑色素瘤治疗有意义。本文的在线版本（doi：10.1186/s12967-014-0247-5）包含补充材料，可供授权用户使用。
Advances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance. The involvement of BRAFV600E in metabolic reprogramming of melanoma cells provides a rationale for co-targeting metabolism as a therapeutic approach. We examined the effects of dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, on the growth and metabolic activity of human melanoma cell lines. The combined effect of DCA and the BRAF inhibitor vemurafenib was investigated in BRAFV600E -mutated melanoma cell lines. Vemurafenib-resistant cell lines were established in vitro and their sensitivity to DCA was tested. DCA induced a reduction in glycolytic activity and intracellular ATP levels, and inhibited cellular growth. Co-treatment of BRAFV600E-mutant melanoma cells with DCA and vemurafenib induced a greater reduction in intracellular ATP levels and cellular growth than either compound alone. In addition, melanoma cells with in vitro acquired resistance to vemurafenib retained their sensitivity to DCA. These results suggest that DCA potentiates the effect of vemurafenib through a cooperative attenuation of energy production. Furthermore, the demonstration of retained sensitivity to DCA in melanoma cells with acquired resistance to vemurafenib could have implications for melanoma treatment. The online version of this article (doi:10.1186/s12967-014-0247-5) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
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作者：
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