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PLoS One. 2014 Feb 25;9(2):e86369. doi: 10.1371/journal.pone.0086369. eCollection 2014.

Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis.

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
2
Department of Radiation Oncology and Otolaryngology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
3
Emory College of Arts and Sciences, Atlanta, Georgia, United States of America.
4
Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia, United States of America.
5
Quest Diagnostics, Atlanta, Georgia, United States of America.

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.

PMID:
24586249
PMCID:
PMC3934844
DOI:
10.1371/journal.pone.0086369
[Indexed for MEDLINE]
Free PMC Article

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