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.
Highlights
Cancer is becoming a major life-threatening global public health problem [1], of which lung cancer as a serious cancer form contributed to 20% of all cancer death cases [2, 3]
Alpha-adenosine menophosphateactivated protein kinase (AMPK) activators are identified by molecular docking on a compound library
All compounds have been analyzed by molecular docking, and tested on H1975 cells which harbor epidermal growth factor receptor (EGFR) T790M/L858R double mutation that confers to gefitinib resistance
Summary
Cancer is becoming a major life-threatening global public health problem [1], of which lung cancer as a serious cancer form contributed to 20% of all cancer death cases [2, 3]. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer and dominates almost 85% of all lung cancer cases. Conventional therapy, such as surgery, chemotherapy, or radiotherapy, scarify normal cells during the curing progress are becoming unfavorable. For the NSCLC patients who harbor activating substitution from leucine to arginine at amino acid 858 (L858R) point mutation and in-frame exon 19 deletion on EGFR, response well to gefitinib and these two common mutation are used a biomarkers for gefitinib prescription. Gefitinib-resistance commonly happens due to www.impactjournals.com/oncotarget further substitution mutation from threonine to methionine at amino acid position 790 (T790M) occurred after one year or less gefitinib treatment. Developing new treatment strategy to tackle gefitinib-resistance is urgently
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