Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells.
The unique bioenergetic feature of cancer, aerobic glycolysis or the Warburg effect, is an attractive therapeutic target for cancer therapy. Reversing the glycolytic phenotype may trigger apoptosis in tumor cells. Recently, dichloroacetate (DCA) was proven to produce significant cytotoxic effects in certain tumor cells through this distinct mechanism. In this study, the effect of DCA on the metabolism of cervical cancer HeLa cells was explored and its synergistic growth inhibition with cisplatin was also evaluated. The intracellular changes in HeLa cells following DCA exposure were analyzed through cell viability, intracellular H2O2 and pH levels, mitochondrial membrane potential (MMP), expression of apoptotic proteins and Kv1.5 channel, and intracellular-free Ca2+ concentration ([Ca2+]i). For the evaluation of combination chemotherapy, HeLa cells were treated with a combination of DCA and cisplatin at various concentrations for 48 h. Cell viability was determined by CCK-8 assay and the synergy of the two agents was evaluated using the R index method. DCA shifted the metabolism of HeLa cells from aerobic glycolysis to glucose oxidation as shown by the increased intracellular H2O2 and pH levels. The change of the metabolism modality led to a drop in MMP and the increase of apoptotic proteins (caspase 3 and 9). The increased Kv1.5 expression and decreased [Ca2+]i established a positive feedback loop that resulted in reduced tonic inhibition of caspases. Combination chemotherapy of DCA and cisplatin exhibited a significant synergy in inhibiting the proliferation of HeLa cells. The specific apoptotic mechanism of DCA as distinguished from the cisplatin may be partly responsible for the synergy and further in vivo study on combination chemotherapy of the two agents in cervical cancer xenografts in mice is warranted.
Department of Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
Jing
J
Xie
Bing-Shun
BS
Wang
De-Hong
DH
Yu
Qin
Q
Lu
Jian
J
Ma
Hong
H
Qi
Chao
C
Fang
Hong-Zhuan
HZ
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction; D014471:Umbilical Veins / Q000378:metabolism
D000970:Antineoplastic Agents; D051666:Kv1.5 Potassium Channel; D003999:Dichloroacetic Acid; D006861:Hydrogen Peroxide; D005947:Glucose; D002945:Cisplatin; D002118:Calcium