Research
Gossypol inhibits non-small cell lung cancer cells proliferation by targeting EGFRL858R/T790M
Dr Elaine Lai Han Leunget al reported thatGossypol inhibits non-small cell lung cancer cells proliferation by targeting EGFRL858R/T790M
Overexpression of epidermal growth factor receptor (EGFR) has been reported to be implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Several EGFR inhibitors have been used in clinical treatment of NSCLC, but the emergence of EGFRL858R/T790Mresistant mutation has reduced the efficacy of the clinical used EGFR inhibitors. There is an urgent need to develop novel EGFRL858R/T790Minhibitors for better NSCLC treatment. By screening a natural product library, we have identified gossypol as a novel potent inhibitor targeting EGFRL858R/T790M. The activity of gossypol on NSCLC cells was evaluated by cell proliferation, cell apoptosis and cell migration assays. Kinase activity inhibition assay and molecular docking were used to study the inhibition mechanism of gossypol to EGFRL858R/T790M. Western blotting was performed to study the molecular mechanism of gossypol inhibiting the downstream pathways of EGFR. Gossypol inhibited the cell proliferation and cell migration of NSCLC cells, and induced caspase-dependent cell apoptosis of NSCLC cells by upregulating the expression of pro-apoptotic protein BAD. Molecular docking revealed that gossypol could bind to the kinase domain of EGFRL858R/T790M with good binding affinity through hydrogen bonds and hydrophobic interactions. Gossypol inhibited the kinase activity of EGFRL858R/T790Mwith EC50 of 150.1 nM. Western blotting analysis demonstrated that gossypol inhibited the phosphorylation of EGFR and its downstream signal pathways in a dose-dependent manner. Gossypol inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting EGFRL858R/T790M. Our findings provided a basis for developing novel EGFRL858R/T790Minhibitors for treatment of NSCLC. This paper was published by the journal “ Frontiers in Pharmacology ” onJuly09, 2018. The newly released Impact Factor for Frontiers in Pharmacology is 4.4 (Thomson Reuters, 2017).
Celastrol Induces Apoptosis in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells via Caspases-Dependent Pathways and Hsp90 Client Protein Degradation
Dr. Elaine LaiHan Leunget al reported that Celastrol Induces Apoptosis in Gefitinib-Resistant Non-Small Cell Lung Cancer Cells via Caspases-Dependent Pathways and Hsp90 Client Protein Degradation
EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small moleculessuch as gefitinib has been used for inhibiting EGFR with good initial responses, however, drug resistance is common when using a mono-targeting strategy.In recently years, they aimed to elucidate the anticancer effects of allkindsofChinese traditional medicine on NSCLC cell lines with KRAS or EGFR mutations.
Celastrol, a triterpene extracted from the Chinese herb Tripterygium wilfordii, has been shown to have multiple bioactivities. Although among these activities, its anticancer effects have attracted the most attention, the effect of celastrol on gefitinib-resistant non-small cell lung cancer (NSCLC) cells is not clearly known.In this study, we examined the potency of celastrol in three different NSCLC cell lines. We explored its treatment mechanism in two gefitinib-resistant NSCLC cell lines (H1650 and H1975). The data demonstrated that celastrol exerted its apoptotic effect in a dose- and time-dependent manner. Also, the mitochondria membrane potential was gradually lost and the ratio of Bax/Bcl-2 increased after the treatment of celastrol, both of which are indicators of mitochondria membrane integrity. Although the caspases were activated, the treatment with pan-caspase inhibitor could partially inhibit the level of apoptosis. Moreover, the protein level of Hsp90 client proteins, EGFR and AKT, was measured. Interestingly, both client proteins were remarkably down-regulated after the treatment of celastrol.
Taken together,this founding discovered indicated that celastrol may be developed as a promising agent for treating gefitinib-resistant NSCLCs by inducing apoptosis through caspase-dependent pathways and Hsp90 client protein degradation.
This paper was publicated by the journal “molecules”, 21 March 2014. The newly released Impact Factor for Frontiers in Pharmacology is 3.09(Thomson Reuters, 2018).
Novel Direct AMPK Activator Suppresses Non-Small Cell Lung Cancer through Inhibition of Lipid Metabolism
Dr Elaine Lai-Han Leung et al reported that a new AMPK agonist can specifically supress non-small cell lung cancer resistant cells viability by inhibition of lipid metabolism.
Non-small cell lung cancer (NSCLC) dominates almost 85% of all lung cancer cases, becoming top 1 killer in the whole world. The patients whom harbor epidermal growth factor receptor (EGFR) mutation become resistant to tyrosine kinase inhibitors (TKIs), such as gefitinib within 1 year treatment. Therefore, it is urgently needed to discover novel effective small molecule inhibitors for those patients. In recently years, lots of scientists claimed cancer cell on different metabolism way. They pointed out that interferance cancer cells metabolism could cut off energy supporting. This concept was become ture by Chair Prof. Liu Liang, Prof. Yao Xiao-Jun, Dr. Leung Lai-Han and their team from the State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology, MUST). They identified a new compound D561-0775 which can inhibit NSCLC TKIs resistance cell growth.
They anchored on a metabolism rate-limiting enzyme 5’-adenosine menophosphate-activated protein kinase (AMPK) as a promising anti-cancer target. Based on AMPK structure, they using molecular docking technique to screen the compound library which contains 12000 compounds. After cell vability and functional in vitro assay, they demonstrated that D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines. Furthermore, D561-0775 showed a remarkable in vitro AMPK enzyme activation effect.
Taken together, D561-0775 displayed potential anti-cancer activity via inducing apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis after activation of AMPK in gefitinib-resistant H1975 cells.
This founding discovered that D561-0775 has provided a new chemical structure. It poteinial could be developed as cancer drug for gefitinib-resistant NSCLC patients through regulating lipid metabolism by directly targeting at AMPK. This paper was publicated by the journal “ Oncotarget ” on October 12, 2017. The newly released Impact Factor for Oncotarget is 5.16 (Thomson Reuters, 2017).
Inhibition of KRAS-dependent Lung Cancer Cell Growth by Deltarasin
Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity
Dr Elaine Lai Han Leung et al reported that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking “tumor protective” autophagy, but inhibited if combined with an anti-oxidant.
Elaine’s group discovered a cardiac glycoside restrains EGFR-related and EGFR-independent NSCLC cell proliferation with distinct treatment mechanism
Non-small cell lung cancer (NSCLC) is the predominant histological type of lung cancer and is characterized by the highest mortality and incidence rates among these types of malignancies (1, 2). Traditional Chinese medicine (TCM) has been applied for centuries in China (3, 4). Cardiac glycosides, a class of natural products, have been identified as a potential type of chemotherapeutic agent (5, 6).
Recently, Elaine’s group has found out a novel anti-cancer effects and the mechanisms of action of Proscillaridin A (P.A) in NSCLC cells. In vitro sodium-potassium pump (Na+/K+ ATPase) enzyme assays indicated that P.A is a direct Na+/K+ ATPase inhibitor. P.A showed potent cytotoxic effects in NSCLC cells at nanomolar levels. Treatment mechanism studies indicated that P.A elevated Ca2+ levels, activated the AMPK pathway and down–regulated phosphorylation of ACC and mTOR. Subsequently, P.A increased death receptor 4 (DR4) expression and down-regulated NF–κB. Interestingly, P.A selectively suppressed EGFR activation in EGFR mutant cells but not in EGFR wild-type cells. In vivo, P.A significantly suppressed tumor growth in nude mice compared to vehicle-treated mice. Compared with the Afatinib treatment group, P.A displayed less pharmaceutical toxicity, as the body weight of mice treated with P.A did not decrease as much as those treated with Afatinib. Consistent changes in protein levels were obtained from Western blotting analysis of tumors and cell lines. Immunohistochemistry analysis of the tumors from P.A-treated mice showed a significant suppression of EGFR phosphorylation (Tyr 1173) and reduction of the cell proliferation marker Ki67. Taken together, our results suggest that P.A is a promising anti-cancer therapeutic candidate for NSCLC.
News mentioned Elaine group’s article:
Proscillaridin A induces apoptosis and suppresses non-small-cell lung cancer tumor growth via calcium-induced DR4 upregulation[J]. Cell Death & Disease, 2018, 9(6):696-.
References:
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(5). Sachs G, Munson K. Mammalian phosphorylating ion-motive ATPases. Current Opinion in Cell Biology. 1991;3(4):685.
(6). Mijatovic T, et al. The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers. Journal of Pathology. 2007;212(2):170-9.