title: Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis.
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.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology and Otolaryngology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Beitler
authors.affiliation: Department of Radiation Oncology and Otolaryngology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Emory College of Arts and Sciences, Atlanta, Georgia, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology and Otolaryngology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Lydia
authors.initials: L
authors.lastname: Koenig
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Nannapaneni
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: A R M Ruhul
authors.initials: AR
authors.lastname: Amin
authors.affiliation: Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonner
authors.affiliation: Quest Diagnostics, Atlanta, Georgia, United States of America.
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia, United States of America.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D017705:Lignans; D017239:Paclitaxel; D053218:Receptors, Death Domain; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C512478:EGFR protein, human