Silybin counteracts doxorubicin resistance by inhibiting GLUT1 expression

Abstract Despite significant advances in the diagnosis and treatment of cancer, the development of drug resistance still remains one of the principal causes that hampers the effectiveness of the therapy. Emerging evidences support the idea that the dysregulated metabolism could be related to drug resistance. The major goal of this study was to target cancer metabolic pathways using new pharmacological approaches coming from natural sources in order to possibly prevent or overcome this phenomenon. Firstly, the metabolic profile of human colorectal adenocarcinoma cells sensitive (LoVo WT) and resistant to doxorubicin (LoVo DOX) was delineated demonstrating that resistant cells remodel their metabolism toward a glycolytic phenotype. In particular it was observed that doxorubicin-resistant cancer cells exhibit an increased dependency from glucose for their survival, associated with overexpression of the glycolytic pathway. Moreover, both GLUT1 mRNA and protein expression significantly increased in LoVo DOX cells. Given the results about the metabolic profile, silybin, modulator of GLUTs, was selected as potential candidate to overcome doxorubicin resistance and, intriguingly, data revealed not only that silybin is more active in resistant cells than in wild type cells, but also that the combined treatment with doxorubicin and silybin presents a synergistic effect in LoVo DOX cells. Although many unanswered questions still remain about the molecular mechanism of silybin, these data suggest that targeting GLUTs may be a good strategy to restore doxorubicin sensitivity and elude drug resistance.