Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism

// Xi Chen 1 , Chun Xie 1 , Xing-Xing Fan 1 , Ze-Bo Jiang 1 , Vincent Kam-Wai Wong 1 , Jia-Hui Xu 1 , Xiao-Jun Yao 1 , Liang Liu 1 and Elaine Lai-Han Leung 1, 2, 3 1 State 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 2 Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Hubei, China 3 Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical College, Guangzhou, China Correspondence to: Elaine Lai-Han Leung, email: lhleung@must.edu.mo Xiao-Jun Yao, email: xjyao@must.edu.mo Liang Liu, email: lliu@must.edu.mo keywords: novel AMPK activator; NSCLC; gefitinib-resistant; lipid metabolism Received: June 27, 2017     Accepted: August 23, 2017     Published: October 09, 2017 ABSTRACT 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.