title: A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.
abstract: Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C(16)H(14)ClN(3)O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.
authors.affiliation: 1] Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China [2] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Chu
authors.affiliation: 1] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China [2] Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China [2] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Ding
authors.affiliation: 1] Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China [2] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.affiliation: The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: Q
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Shen
authors.affiliation: 1] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China [2] Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 1] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China [2] Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Tan
authors.affiliation: 1] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China [2] Shenzhen Anti-Tumor Drug Development Engineering Laboratory, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China [3] Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C031000:benzimidazole; C512478:EGFR protein, human; C508053:ERBB2 protein, human