title: Evodiamine induces apoptosis and enhances apoptotic effects of erlotinib in wild-type EGFR NSCLC cells via S6K1-mediated Mcl-1 inhibition.
abstract: Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib.
authors.affiliation: Department of Clinical Pharmacy, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China.|Department of Clinical Pharmacy, Affiliated Hangzhou Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China.
authors.forename: Yang-Ling
authors.initials: YL
authors.lastname: Li
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Yi-Ni
authors.initials: YN
authors.lastname: Pan
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Wen-Jue
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Mao
authors.affiliation: Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Sun
authors.affiliation: Emergency Room, Sir Run Run Shaw Hospital Affiliated to Medical College of Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhao
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Jing-Yin
authors.initials: JY
authors.lastname: Dong
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Pan
authors.affiliation: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. zhangchong@zucc.edu.cn.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacy, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China. lnm1013@163.com.|Department of Clinical Pharmacy, Affiliated Hangzhou Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. lnm1013@163.com.|Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China. lnm1013@163.com.
authors.forename: Neng-Ming
authors.initials: NM
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011799:Quinazolines; C049639:evodiamine; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: Combination; Erlotinib; Evodiamine; Mcl-1; NSCLC