title: Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers.
abstract: Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated whether garcinol, a polyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin. We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines, enhanced the apoptotic effect of cisplatin, suppressed constitutive as well as cisplatin-induced NF-κB activation, and downregulated the expression of various oncogenic gene products (cyclin D1, Bcl-2, survivin and VEGF). In vivo study showed that administration of garcinol alone (0.5 mg/kg body weight, i.p. five times/week) significantly suppressed the growth of the tumor, and this effect was further increased by cisplatin. Both the markers of proliferation index (Ki-67) and microvessel density (CD31) were downregulated in tumor tissues by the combination of cisplatin and garcinol. The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after i.p. administration of garcinol at 0.5 mg/kg and 2 mg/kg with mean peak concentration (Cmax) of 1825.4 and 6635.7 nM in the mouse serum, respectively. Overall, our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Tina H
authors.initials: TH
authors.lastname: Ong
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.|Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Ser Yue
authors.initials: SY
authors.lastname: Loo
authors.affiliation: Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Bangalore, India.
authors.forename: Mahadeva M M
authors.initials: MM
authors.lastname: Swamy
authors.affiliation: Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Bangalore, India.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.|School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia.|Department of Biological Sciences, University of North Texas, Denton, Texas, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.|Department of Haematology-Oncology, National University Health System, Singapore.
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Bangalore, India.
authors.forename: Tapas
authors.initials: T
authors.lastname: Kundu
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore.
authors.forename: Ling Zhi
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D010936:Plant Extracts; D012333:RNA, Messenger; D013729:Terpenes; D002945:Cisplatin; C054597:garcinol
keywords: HNSCC; NF-κB; chemoresistance; garcinol; proliferation