title: Berberine inhibits EGFR signaling and enhances the antitumor effects of EGFR inhibitors in gastric cancer.
abstract: Cetuximab plus chemotherapy for advanced gastric cancer (GC) shows an active result in phase 2 trials. Unfortunately, Combination of cetuximab does not provide enough benefit to chemotherapy alone in phase 3 trials. Studies have demonstrated that berberine can suppress the activation of EGFR in tumors. In this study, we evaluated whether berberine could enhance the effects of EGFR-TKIs in GC cell lines and xenograft models. Our data suggest that berberine could effectively enhance the activity of erlotinib and cetuximab in vitro and in vivo. Berberine was found to inhibit growth in GC cell lines and to induce apoptosis. These effects were linked to inhibition of EGFR signaling activation, including the phosphorylation of STAT3. The expressions of Bcl-xL and Cyclind1 proteins were decreased, whereas the levels of cleavage of poly-ADP ribose polymerase (PARP) were considerably increased in the cell lines in response to berberine treatment. These results suggest a potential role for berberine in the treatment of GC, particularly in combination with EGFR-TKIs therapy. Berberine may be a competent therapeutic agent in GC where it can enhance the effects of EGFR inhibitors.
authors.affiliation: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Junxiong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhangqian
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Haichao
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.|State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D001599:Berberine; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; STAT3; berberine; cetuximab; gastric cancer