Olszewski Ulrike, Poulsen Thomas Tuxen, Ulsperger Ernst, Poulsen Hans Skovgard, Geissler Klaus, Hamilton Gerhard
Ludwig Boltzmann Cluster of Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria.
Clin Pharmacol. 2010;2:177-83. doi: 10.2147/CPAA.S11795. Epub 2010 Sep 14.
Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), and thus promotes glucose oxidation over glycolysis and induces apoptotic death of tumor cells. The present study investigated the potential of DCA to increase the antitumor effects of platinum- based compounds against a panel of permanent cell lines, including small cell lung cancer (SCLC), ovarian cancer, and Ewing's sarcoma in vitro.
DCA at a concentration of 10 mM was combined with cisplatin, carboplatin, satraplatin, the satraplatin metabolite JM118, oxaliplatin, oxoplatin, and picoplatin, and the cytotoxic activity was evaluated in proliferation tests employing a panel of different cell lines. Additionally, cells were pretreated with DCA and then exposed to the platinum drugs and etoposide, or incubated with cisplatin or etoposide followed by application of DCA, respectively.
DCA 10 mM significantly increased the cytotoxicity of the platinum-based drugs carboplatin, satraplatin, JM118, and oxoplatin, but not cisplatin, picoplatin, and oxaliplatin in vitro. Preincubation of cell lines with DCA 10 mM for three days reduced the antiproliferative activity of platinum-based agents in sequential application, but exposure of cells pretreated with cisplatin or etoposide to DCA resulted in minor sensitization. The inhibitory effect of DCA showed no correlation with sensitization to the platinum compounds.
DCA alone in a concentration that shows low antiproliferative activity is capable of increasing the cytotoxicity of selected platinum compounds upon coincubation, and such combinations may be interesting for clinical application in tumors like SCLC, Ewing's sarcoma, and ovarian cancer refractory to cisplatin chemotherapy as standard care. The mechanism of this synergistic effect of DCA in combination with specific platinum species remains to be investigated.
二氯乙酸（DCA）可抑制丙酮酸脱氢酶激酶（PDK），从而促进葡萄糖氧化而非糖酵解，并诱导肿瘤细胞凋亡死亡。本研究在体外研究了DCA增强铂类化合物对一组永久细胞系（包括小细胞肺癌（SCLC）、卵巢癌和尤因肉瘤）抗肿瘤作用的潜力。
将浓度为10 mM的DCA与顺铂、卡铂、沙铂、沙铂代谢产物JM118、奥沙利铂、奥铂和匹铂联合使用，并在使用一组不同细胞系的增殖试验中评估细胞毒性活性。此外，细胞先用DCA预处理，然后分别暴露于铂类药物和依托泊苷，或先与顺铂或依托泊苷孵育，随后再应用DCA。
10 mM的DCA在体外显著增强了铂类药物卡铂、沙铂、JM118和奥铂的细胞毒性，但对顺铂、匹铂和奥沙利铂无此作用。用10 mM的DCA对细胞系进行三天的预孵育会降低铂类药物序贯应用时的抗增殖活性，但将先用顺铂或依托泊苷预处理的细胞暴露于DCA会导致轻微的致敏作用。DCA的抑制作用与对铂类化合物的致敏作用无关。
单独使用时显示出低抗增殖活性的DCA浓度能够在共同孵育时增强所选铂类化合物的细胞毒性，这种联合用药可能对小细胞肺癌、尤因肉瘤和对顺铂化疗作为标准治疗无效的卵巢癌等肿瘤的临床应用具有意义。DCA与特定铂类药物联合产生这种协同作用的机制仍有待研究。
