A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells

Cell Death & Disease
B ChuY Jiang

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 canc...Continue Reading

References

Feb 16, 1996·Journal of Medicinal Chemistry·J S KimE J LaVoie
Aug 28, 1998·Science·A Ashkenazi, V M Dixit
Oct 16, 1999·The Journal of Biological Chemistry·M P ScheidV Duronio
Apr 27, 2000·Nature Cell Biology·J L BodmerJ Tschopp
Mar 17, 2001·Nature Reviews. Molecular Cell Biology·Y Yarden, M X Sliwkowski
Mar 15, 2002·Seminars in Oncology·Wilbur A FranklinPaul A Bunn
Oct 7, 2003·Oncogene·Sylvie MénardElda Tagliabue
Jan 30, 2004·Cancer Immunology, Immunotherapy : CII·Klaus-Michael Debatin
May 3, 2005·Nature Reviews. Cancer·Nancy E Hynes, Heidi A Lane
Oct 21, 2005·The New England Journal of Medicine·Martine J Piccart-GebhartUNKNOWN Herceptin Adjuvant (HERA) Trial Study Team
Oct 21, 2005·The New England Journal of Medicine·Edward H RomondNorman Wolmark
May 27, 2006·Endocrine-related Cancer·Marc LacroixGuy Leclercq
May 27, 2006·Molecular Systems Biology·Waltraud X SchulzeMatthias Mann
Nov 23, 2006·Cellular Signalling·Sachie AsadaAkiyoshi Fukamizu
Feb 28, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ronald KoschnyHenning Walczak
Oct 17, 2007·Bioorganic & Medicinal Chemistry Letters·Danielle K NeffJ Guy Breitenbucher
Jan 22, 2008·Nature Cell Biology·Jer-Yen YangMien-Chie Hung
May 8, 2008·Particle and Fibre Toxicology·Jamshid PourazarThomas Sandström
Feb 18, 2010·Cell Cycle·Anthony C FaberJeffrey A Engelman
Apr 14, 2010·Journal of Controlled Release : Official Journal of the Controlled Release Society·Wanyi TaiKun Cheng
Jul 7, 2010·Cell·Mark A Lemmon, Joseph Schlessinger
Jun 10, 2011·Science Translational Medicine·Nathan G DolloffWafik S El-Deiry
May 9, 2012·Chemical Biology & Drug Design·Soni YadavVinay K Singh
Jul 13, 2012·Nature Reviews. Cancer·Yosef Yarden, Gur Pines
Oct 18, 2012·Breast Cancer Research and Treatment·Hiroko MasudaNaoto T Ueno
Jan 8, 2013·Nature Chemical Biology·Gelin WangXiaodong Wang
Mar 22, 2014·Cancer Cell·Patricia A J Muller, Karen H Vousden

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Citations

Nov 28, 2015·Endocrine-related Cancer·Martyn Bullock
Oct 27, 2017·Cell Death & Disease·Hongzhi DuLi Sun
May 23, 2018·International Journal of Molecular Sciences·Abhishek GangradeDonald J Buchsbaum
Sep 8, 2018·Proceedings of the National Academy of Sciences of the United States of America·Bizhu ChuRuijun Tian
Oct 16, 2021·Chemical Biology & Drug Design·Mar'iyah Najihah AbdullahShafida Abd Hamid

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Methods Mentioned

BETA
PCR
xenograft

Software Mentioned

MAS3
SAM
LuxScan

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