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

• Published in: PloS one Vol. 9; no. 2; p. e86369
• Main Authors: Wang, Xu, Beitler, Jonathan J, Wang, Hong, Lee, Michael J, Huang, Wen, Koenig, Lydia, Nannapaneni, Sreenivas, Amin, A R M Ruhul, Bonner, Michael, Shin, Hyung Ju C, Chen, Zhuo Georgia, Arbiser, Jack L, Shin, Dong M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.02.2014; Public Library of Science (PLoS)
• Subjects: Analysis; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biocompatibility; Biology; Biphenyl Compounds - pharmacology; Cancer; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Combined treatment; Cytotoxicity; Dermatology; Down-Regulation - drug effects; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Drug therapy; Drugs; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Health aspects; Hematology; Humans; Inhibition; KB cells; Ki-67 Antigen - metabolism; Lignans - pharmacology; Medical research; Medicine; Microbial drug resistance; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Multidrug resistance; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Otolaryngology; Paclitaxel; Paclitaxel - pharmacology; Parenting; Receptors, Death Domain - metabolism; Rodents; Signal Transduction - drug effects; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; Tissues; Toxicity; Tumor cell lines; Tumors; Atlanta Georgia; United States > US; Georgia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086369

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.