title: Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors.
abstract: OBJECTIVE
  Aberrant human epidermal growth factor receptor-2 (HER2) expression and constitutive mutant activation of its tyrosine kinase domain account for tumor aggression and therapy resistance in many types of cancers with major share in breast cancer cases. HER2 specific treatment modalities still face challenges owing to the side effects and acquired resistance of available therapeutics. Recently, the anti-proliferative and pro-apoptotic potential of phytochemicals, especially of flavonoids have become increasingly appreciated as powerful chemo preventive agents. Consequently, the major goal of our study is to identify flavonoids capable of inhibiting HER2 Tyrosine Kinase (HER2-TK) activity and validate their anti-tumor activity against HER2 positive tumors.
  
  
  METHODS
  Molecular docking studies for identifying flavonoids binding at HER2 kinase domain, ADP-Glo™ Kinase Assay for determining kinase activity, MTT assay to measure growth inhibition, various apoptotic assays and cell cycle analysis by FACS were performed.
  
  
  RESULTS
  Among the flavonoids screened, Naringenin (NG) and Hesperetin (HP) possessed high glide scores from molecular docking studies of enzyme-inhibitor mode. The interaction analysis revealed their ability to establish stable and strong interaction at the ATP binding site of HER2-TK. These compounds also inhibited in vitro HER2-TK activity suggesting their role as HER2 inhibitors. The study also unraveled the anti-proliferative, pro-apoptotic and anti-cancerous activity of these flavonoids against HER2 positive breast cancer cell line.
  
  
  CONCLUSIONS
  The study identified two citrus fruit flavonoids, NG and HP as HER2-TK inhibitors and this is the first report on their potential to target preferentially and sensitize HER2 positive cancer cells to cell death.
authors.affiliation: Inter University Centre for Bioscience and Department of Biotechnology & Microbiology, Kannur University Thalassery Campus, Kannur 670 661, Kerala, India. Electronic address: bhavyabc@gmail.com.
authors.forename: Bhavya Balan
authors.initials: BB
authors.lastname: Chandrika
authors.affiliation: Govt Brennen College, Kannur University, Kannur 670 661, Kerala, India.
authors.forename: Mathew
authors.initials: M
authors.lastname: Steephan
authors.affiliation: Rajiv Gandhi Centre for Biotechnology, Trivandrum 695014, Kerala, India.
authors.forename: T R Santhosh
authors.initials: TRS
authors.lastname: Kumar
authors.affiliation: Inter University Centre for Bioscience and Department of Biotechnology & Microbiology, Kannur University Thalassery Campus, Kannur 670 661, Kerala, India.
authors.forename: A
authors.initials: A
authors.lastname: Sabu
authors.affiliation: Inter University Centre for Bioscience and Department of Biotechnology & Microbiology, Kannur University Thalassery Campus, Kannur 670 661, Kerala, India. Electronic address: mharidasm@rediffmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Haridas
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D044950:Flavanones / Q000494:pharmacology*; D018734:Genes, erbB-2; D006569:Hesperidin / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D044950:Flavanones; D047428:Protein Kinase Inhibitors; D006569:Hesperidin; D011505:Protein-Tyrosine Kinases; C005273:naringenin; C013015:hesperetin
keywords: Anti-cancer agents; Flavonoids; HER2 positive; HER2-TK; HER2-Tyrosine Kinase inhibitors; Hesperetin; Naringenin