title: Garcinol sensitizes breast cancer cells to Taxol through the suppression of caspase-3/iPLA2and NF-κB/Twist1 signaling pathways in a mouse 4T1 breast tumor model.
abstract: Breast cancer is a significant threat to women's health and has high incidence and mortality. Metastasis in breast cancer patients is a major cause of cancer deaths among women worldwide. Clinical experience suggests that patients with metastatic triple-negative breast cancer (TNBC) relapse quickly and often have chemotherapy resistance. Taxol (paclitaxel) is an effective chemotherapeutic agent for treating metastatic breast cancer, but Taxol at high doses can cause adverse effects and recurrent resistance. Thus, the selection of a synergistic combination therapy is recommended, which is safer and has a more significant response rate than monotherapy. In this study, our strategy is to combine a low dose of Taxol (5 mg kg-1, i.p.) and garcinol (1 mg kg-1, i.g.) to investigate the synergistic antitumor and anti-metastasis effects and to determine the underlying mechanisms of these effects in vivo. For the in vivo study, metastasis-specific mouse mammary carcinoma 4T1 cells were inoculated in Balb/c mice to establish an orthotopic primary tumor and spontaneous metastasis model. Tumor growth and metastases were monitored. The mechanisms of synergistic efficacies were evaluated at different signaling pathways, including proliferation, survival, and epithelial-mesenchymal transition (EMT)-regulated metastatic propensity. We demonstrated that garcinol combined with Taxol significantly increased the therapeutic efficacy when compared with either treatment alone. The synergistic antitumor and anti-metastasis effects were enhanced primarily through the induction of Taxol-stimulated G2/M phase arrest and the inhibition of caspase-3/cytosolic Ca2+-independent phospholipase A2 (iPLA2) and nuclear factor-κB (NF-κB)/Twist-related protein 1 (Twist1) drive downstream events including tumor cell repopulation, survival, inflammation, angiogenesis, invasion, and EMT. Our current findings provide the first experimental evidence that a combination of a low dose of Taxol and garcinol is a promising therapeutic strategy for controlling advanced or metastatic breast cancer. Finally, our results also point to the possible role of NF-κB/Twist1 and caspase-3/iPLA2signaling pathways as biomarkers to predict the tumor response to treatment.
authors.affiliation: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan and Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan and Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Tu
authors.affiliation: Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan. mhpan@ntu.edu.tw.
authors.forename: Yi-Shiou
authors.initials: YS
authors.lastname: Chiou
authors.affiliation: Sabinsa Corporation, East Windsor, NJ 08520, USA.
authors.forename: Nagabhushanam
authors.initials: N
authors.lastname: Kalyanam
authors.affiliation: Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan and TMU Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. lcchen@tmu.edu.tw and Cancer Translational Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan. mhpan@ntu.edu.tw and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan and Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Min-Hsiung
authors.identifier: http://orcid.org/0000-0002-5188-7030
authors.initials: MH
authors.lastname: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D029760:Garcinia; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage*; D010936:Plant Extracts / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000008:administration & dosage*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010936:Plant Extracts; D013729:Terpenes; D051879:Twist-Related Protein 1; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D053148:Caspase 3; D017239:Paclitaxel; C054597:garcinol