Anti-cancer synergy of dichloroacetate and EGFR tyrosine kinase inhibitors in NSCLC cell lines
详细信息 查看全文
- 作者：Zheng Yang ; Kin Y. Tam ; kintam@umac.mo" class="auth_mail" title="E-mail the corresponding author
- 关键词：Pyruvate dehydrogenase kinase ; Dichloroacetate ; Epidermal growth factor Receptor ; Erlotinib ; Gefitinib ; Drug combination
- 刊名：European Journal of Pharmacology
- 出版年：2016
- 出版时间：15 October 2016
- 年：2016
- 卷：789
- 期：Complete
- 页码：458-467
- 全文大小：2930 K
文摘
Glycolysis has been observed as a predominant process for most cancer cells to utilize glucose, which was referred to as “Warburg Effect”. Targeting critical enzymes, such as pyruvate dehydrogenase kinase (PDK) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. EGFR inhibitors for Non-Small-Cell Lung Cancer (NSCLC) treatment have been applied for decades in clinical practices with great success, but also their clinical benefits were somewhat hampered by the rising acquired-resistance. Combination drug therapy is an effective strategy to cope with the challenge. In this study, we utilized Dichloroacetate (DCA), a widely regarded PDK inhibitor, together with Erlotinib and Gefitinib, two well-known EGFR inhibitors, and demonstrated that the applications of DCA in combination with either Erlotinib or Gefitinib significantly attenuated the viability of EGFR mutant NSCLC cells (NCI-H1975 and NCI-H1650) in a synergistic manner. This synergistic outcome appears to be a combination effect in promoting apoptosis, rather than co-suppression of either EGFR or PDK signaling pathways. Moreover, we have shown that the combination treatment did not exhibit synergistic effect in other NSCLC cell lines without EGFR mutations (A549 or NCI-H460). Together, these observations suggested that combined targeting of EGFR and PDK in NSCLC cells exerted synergistic effects in an EGFR mutation-dependent fashion.