Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

// Feng Li 1 , Muthu K. Shanmugam 1 , Kodappully Sivaraman Siveen 1 , Fan Wang 1, 2 , Tina H. Ong 3 , Ser Yue Loo 1, 2, 4 , Mahadeva M.M. Swamy 5 , Somnath Mandal 5 , Alan Prem Kumar 1, 2, 6, 7 , Boon Cher Goh 1, 2, 8 , Tapas Kundu 5 , Kwang Seok Ahn 9 , Ling Zhi Wang 1, 2 , Kam Man Hui 3 , Gautam Sethi 1, 6 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore 3 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 4 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 5 Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Bangalore, India 6 School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia 7 Department of Biological Sciences, University of North Texas, Denton, Texas, USA 8 Department of Haematology-Oncology, National University Health System, Singapore 9 College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea Correspondence to: Gautam Sethi, e-mail: phcgs@nus.edu.sg Kam Man Hui, e-mail: cmrhkm@nccs.com.sg Ling Zhi Wang, e-mail: csiwl@nus.edu.sg Keywords: HNSCC, chemoresistance, NF-κB, proliferation, garcinol Received: June 30, 2014      Accepted: December 08, 2014      Published: February 28, 2015 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.