Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition

Journal of Translational Medicine

Per Guldberg²  Tao Ma¹  Astrid L Basse¹  Christina Dahl²  Cecilie Abildgaard² 

[1] Department of Biology, University of Copenhagen, Copenhagen, Denmark;Danish Cancer Society Research Center, Copenhagen, Denmark

关键词: ATP;    Metabolism;    Bioenergetics;    BRAF;    Melanoma;    Dichloroacetate;   

Others  :  1148224
DOI  :  10.1186/s12967-014-0247-5

 received in 2014-04-23, accepted in 2014-08-28,  发布年份 2014

【 摘 要 】

Background

Advances in melanoma treatment through targeted inhibition of oncogenic BRAF are limited owing to the development of acquired resistance. The involvement of BRAF^V600E in metabolic reprogramming of melanoma cells provides a rationale for co-targeting metabolism as a therapeutic approach.

Methods

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 BRAF^V600E -mutated melanoma cell lines. Vemurafenib-resistant cell lines were established in vitro and their sensitivity to DCA was tested.

Results

DCA induced a reduction in glycolytic activity and intracellular ATP levels, and inhibited cellular growth. Co-treatment of BRAF^V600E-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.

Conclusions

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.

【 授权许可】

   
2014 Abildgaard et al.; licensee BioMed Central Ltd.

【 图 表 】

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