title: EGFR inhibition by pentacyclic triterpenes exhibit cell cycle and growth arrest in breast cancer cells.
abstract: OBJECTIVE
  Pentacyclic triterpenes are a group of molecules with promising anticancer potential, although their precise molecular target remains elusive. The current work aims to investigate the antiproliferative and associated mechanisms of triterpenes in breast cancer cells in vitro.
  
  
  METHODS
  Effect of triterpenes on cell cycle distribution, ROS and key regulatory proteins were analyzed in three breast cancer cells in vitro. Growth inhibition, new DNA synthesis, colony formation assays and Western blot analysis were performed to assess the EGFR inhibitory effect of triterpenes. Molecular docking was performed to study the interaction between EGFR and triterpenes.
  
  
  RESULTS
  We have demonstrated the ability of dimethyl melaleucate (DMM), a pentacyclic triterpene to exhibit cell cycle arrest at G0/G1 phase by down-regulation of cyclin D1 through PI3K/AKT inhibition. Further, to identify the upstream target of DMM, potential EGFR inhibitory activity of DMM and three structurally related pentacyclic triterpenes, ursolic acid, 18α-glycyrrhetinic acid and carbenoxolone was investigated. Interestingly, pentacyclic triterpenes limit EGF mediated breast cancer proliferation through sustained inhibition of EGFR and its downstream effectors STAT3 and cyclin D1 in breast cancer lines. We also show pentacyclic triterpenes to bind at the ATP binding pocket of tyrosine kinase domain of EGFR leading to the hypothesis that pentacyclic triterpenes could be a novel class of EGFR inhibitors. In conclusion, pentacyclic triterpenes inhibit EGFR activation through binding with tyrosine kinase domain thereby suppressing breast cancer proliferation.
  
  
  CONCLUSIONS
  Pentacyclic triterpenes may serve as a potential platform for development of novel drugs against breast cancer.
authors: Tissue Culture and Drug Discovery Laboratory, Centre for Biotechnology, Anna University, Chennai, India.
authors: Shanmugaraj
authors: S
authors: Sathya
authors: Tissue Culture and Drug Discovery Laboratory, Centre for Biotechnology, Anna University, Chennai, India.
authors: Selvaraj
authors: S
authors: Sudhagar
authors: Tissue Culture and Drug Discovery Laboratory, Centre for Biotechnology, Anna University, Chennai, India.
authors: Baskaran
authors: B
authors: Sarathkumar
authors: Tissue Culture and Drug Discovery Laboratory, Centre for Biotechnology, Anna University, Chennai, India. Electronic address: lakshmibs@annauniv.edu.
authors: Baddireddi Subhadra
authors: BS
authors: Lakshmi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D004247:DNA; D066246:ErbB Receptors
keywords: Breast cancer; Cyclin D1; EGFR; PI3K/AKT; Pentacyclic triterpenes; STAT3