Anti-cancer synergy of dichloroacetate and EGFR tyrosine kinase inhibitors in NSCLC cell lines.

Abstract

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.

• Authors: Zheng Yang, Kin Y Tam
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 789 Pg. 458-467 (Oct 15 2016) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 27514773 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Dichloroacetic Acid
• ErbB Receptors
• Matrix Metalloproteinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dichloroacetic Acid (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Humans
• Lung Neoplasms (pathology)
• Matrix Metalloproteinases (metabolism)
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)