Oncotarget

Research Papers:

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors

Jung Min Song, Arunkumar Anandharaj, Pramod Upadhyaya, Ameya R. Kirtane, Jong-Hyuk Kim, Kwon Ho Hong, Jayanth Panyam and Fekadu Kassie _

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Oncotarget. 2016; 7:57752-57769. https://doi.org/10.18632/oncotarget.10759

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Abstract

Jung Min Song1, Arunkumar Anandharaj1, Pramod Upadhyaya1, Ameya R. Kirtane2, Jong-Hyuk Kim1,4, Kwon Ho Hong3, Jayanth Panyam1,2, Fekadu Kassie1,4

1Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

2Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA

3Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA

4Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA

Correspondence to:

Fekadu Kassie, email: [email protected]

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.


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