Honokiol Enhances Paclitaxel Efficacy in Multi-Drug Resistant Human Cancer Model through the Induction of Apoptosis

• Type of Material: Article
• Authors: Xu Wang, Emory University; Jonathan J Beitler, Emory University; Hong Wang, Emory University; Michael J. Lee, Emory University; Wen Huang, Emory University; Lydia Koenig, Emory University; Sreenivas Nannapaneni, Emory University; A R M Ruhul Amin, Emory University; Michael Y. Bonner, Emory University; Hyung Ju C. Shin, Quest Diagnostics; Georgia Chen, Emory University; Jack Arbiser, Emory University; Dong M Shin, Emory University
• Language: English
• Date: 2014
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Wang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0086369
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 2
• Start Page: e86369
• End Page: e86369
• Grant/Funding Information: This work was funded by the National Cancer Institute (NCI) through a Head and Neck Cancer SPORE award (P50CA128613), P30 CA138292, and AR47901.; D.M.S., J.J.B., and Z.G.C. would also like to acknowledge the Georgia Cancer Coalition for support.
• Research Categories: Health Sciences, Oncology; Health Sciences, General

Abstract

Resistance to chemotherapy remains a major obstacle in cancer therapy. This study aimed to evaluate the molecular mechanism and efficacy of honokiol in inducing apoptosis and enhancing paclitaxel chemotherapy in pre-clinical multi-drug resistant (MDR) cancer models, including lineage-derived human MDR (KB-8-5, KB-C1, KB-V1) and their parental drug sensitive KB-3-1 cancer cell lines. In vitro analyses demonstrated that honokiol effectively inhibited proliferation in KB-3-1 cells and the MDR derivatives (IC50 ranging 3.35±0.13 µg/ml to 2.77±0.22 µg/ml), despite their significant differences in response to paclitaxel (IC50 ranging 1.66±0.09 ng/ml to 6560.9±439.52 ng/ml). Honokiol induced mitochondria-dependent and death receptor-mediated apoptosis in MDR KB cells, which was associated with inhibition of EGFR-STAT3 signaling and downregulation of STAT3 target genes. Combined treatment with honokiol and paclitaxel synergistically augmented cytotoxicity in MDR KB cells, compared with treatment with either agent alone in vitro. Importantly, the combined treatment significantly inhibited in vivo growth of KB-8-5 tumors in a subcutaneous model. Tumor tissues from the combination group displayed a significant inhibition of Ki-67 expression and an increase in TUNEL-positive cells compared with the control group. These results suggest that targeting multidrug resistance using honokiol in combination with chemotherapy drugs may provide novel therapeutic opportunities.