title: Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.
abstract: Since epidermal growth factor receptor (EGFR) is commonly deregulated in pre-malignant lung epithelium, targeting EGFR may arrest the development of lung cancer. Here, we showed that honokiol (2.5-7.5 μM), a bioactive compound of Magnolia officinalis, differentially suppressed proliferation (up to 93%) and induced apoptosis (up to 61%) of EGFR overexpressing tumorigenic bronchial cells and these effects were paralleled by downregulation of phospho-EGFR, phospho-Akt, phospho-STAT3 and cell cycle-related proteins as early as 6-12 h post-treatment. Autocrine secretion of EGF sensitized 1170 cells to the effects of honokiol. Molecular docking studies indicated that honokiol binds to the tyrosine kinase domain of EGFR although it was less efficient than erlotinib. However, the anti-proliferative and pro-apoptotic activities of honokiol were stronger than those of erlotinib. Upon combinatory treatment, honokiol sensitized bronchial cells and erlotinib resistant H1650 and H1975 cells to erlotinib. Furthermore, in a mouse lung tumor bioassay, intranasal instillation of liposomal honokiol (5 mg/kg) for 14 weeks reduced the size and multiplicity (49%) of lung tumors and the level of total- and phospho-EGFR, phospho-Akt and phospho-STAT3. Overall, our results indicate that honokiol is a promising candidate to suppress the development and even progression of lung tumors driven by EGFR deregulation.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Song
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Anandharaj
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ameya R
authors.initials: AR
authors.lastname: Kirtane
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA.
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: Kwon Ho
authors.initials: KH
authors.lastname: Hong
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA.
authors.forename: Fekadu
authors.initials: F
authors.lastname: Kassie
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001681:Biological Assay; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001980:Bronchi / Q000378:metabolism; D063646:Carcinogenesis; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D017705:Lignans / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D031566:Magnolia / Q000737:chemistry; D051379:Mice; D062105:Molecular Docking Simulation; D009602:Nitrosamines / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D017705:Lignans; D009602:Nitrosamines; D010936:Plant Extracts; D034741:RNA, Small Interfering; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C512478:EGFR protein, human
keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; EGFR; chemoprevention; honokiol; lung tumor