Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

// Jung Min Song 1 , Arunkumar Anandharaj 1 , Pramod Upadhyaya 1 , Ameya R. Kirtane 2 , Jong-Hyuk Kim 1, 4 , Kwon Ho Hong 3 , Jayanth Panyam 1, 2 , Fekadu Kassie 1, 4 1 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA 2 Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA 3 Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA 4 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA Correspondence to: Fekadu Kassie, email: kassi012@umn.edu Keywords: chemoprevention, honokiol, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, lung tumor, EGFR Received: April 26, 2016      Accepted: July 10, 2016      Published: July 21, 2016 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.