Molecular Carcinogenesis 2015-04-01

Butein, a novel dual inhibitor of MET and EGFR, overcomes gefitinib-resistant lung cancer growth.

Sung Keun Jung, Mee-Hyun Lee, Do Young Lim, Sung Young Lee, Chul-Ho Jeong, Jong Eun Kim, Tae Gyu Lim, Hanyong Chen, Ann M Bode, Hyong Joo Lee, Ki Won Lee, Zigang Dong

Index: Mol. Carcinog. 54(4) , 322-31, (2015)

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Abstract

Lung cancer is a leading cause of death worldwide and MET amplification is a major therapeutic limitation in acquired-resistance lung cancer. We hypothesized that butein, a phytochemical, can overcome gefitinib-induced resistance by targeting both EGFR and MET in non-small cell lung cancer (NSCLC). To investigate the ability of butein to target EGFR and MET, we used in silico docking, a library of natural compounds and kinase assays. The effects of butein on growth, induction of apoptosis and expression of EGFR/MET signaling targets were examined in HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) NSCLC cells. Results were confirmed in vivo by a HCC827 or HCC827GR cell xenograft mouse model, each treated with vehicle, butein or gefitinib. Butein inhibited phosphorylation and kinase activity of EGFR and MET as well as soft agar colony formation and decreased viability of HCC827 and HCC827GR cells. Butein increased apoptosis-related protein expression in these cells. Results were confirmed by co-treatment with inhibitors of EGFR/MET or double knock-down. Finally, xenograft study results showed that butein strongly suppressed HCC827 and HCC827GR tumor growth. Immunohistochemical data suggest that butein inhibited Ki-67 expression. These results indicate that butein has potent anticancer activity and targets both EGFR and MET in acquired-resistance NSCLC.© 2014 Wiley Periodicals, Inc.