Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 38, Issue 2, Pages 409-417Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2010.851
Keywords
dichloroacetate; HeLa cells; metabolism; cisplatin; combination chemotherapy
Categories
Funding
- National Natural Science Foundation of China [30672442, 30600788, 30873179]
- National Basic Research Program of China (973 Program) [2010CB529806]
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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 He La cells was explored and its synergistic growth inhibition with cisplatin was also evaluated. The intracellular changes in He La 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, He La 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 He La 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 He La 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.
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