Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism
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Xi Chen1, Chun Xie1, Xing-Xing Fan1, Ze-Bo Jiang1, Vincent Kam-Wai Wong1, Jia-Hui Xu1, Xiao-Jun Yao1, Liang Liu1 and Elaine Lai-Han Leung1,2,3
1State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR, China
2Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Hubei, China
3Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou, China
Elaine Lai-Han Leung, email: [email protected]
Xiao-Jun Yao, email: [email protected]
Liang Liu, email: [email protected]
keywords: novel AMPK activator; NSCLC; gefitinib-resistant; lipid metabolism
Received: June 27, 2017 Accepted: August 23, 2017 Published: October 09, 2017
Drug resistance is becoming an obstacle in anti-cancer therapies. For target-based therapy of lung cancer, gefitinib, as the first generation of tyrosine kinase inhibitors (TKIs), demonstrated good initial response to the non-small cell lung cancer (NSCLC) patients whom harbors epidermal growth factor receptor (EGFR) mutation. However, within one year, additional EGFR mutation occurred, leading to eventual gefitinib-resistance. Therefore, it is urgently to discover novel effective small molecule inhibitors for those patients. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have identified a novel direct AMPK agonist, D561-0775 from a compound library by using molecular docking screening technique. We demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but less cytotoxicity on normal cells. Furthermore, D561-0775 demonstrated a remarkable in vitro AMPK enzyme activation effect. Taken together, D561-0775 showed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells. D561-0775 has provided a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly.
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