Oncotarget

Research Papers:

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

Feng Li _, Muthu K. Shanmugam, Kodappully Sivaraman Siveen, Fan Wang, Tina H. Ong, Ser Yue Loo, Mahadeva M.M. Swamy, Somnath Mandal, Alan Prem Kumar, Boon Cher Goh, Tapas Kundu, Kwang Seok Ahn, Ling Zhi Wang, Kam Man Hui and Gautam Sethi

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Oncotarget. 2015; 6:5147-5163. https://doi.org/10.18632/oncotarget.2881

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Abstract

Feng Li1, Muthu K. Shanmugam1, Kodappully Sivaraman Siveen1, Fan Wang1,2, Tina H. Ong3, Ser Yue Loo1,2,4, Mahadeva M.M. Swamy5, Somnath Mandal5, Alan Prem Kumar1,2,6,7, Boon Cher Goh1,2,8, Tapas Kundu5, Kwang Seok Ahn9, Ling Zhi Wang1,2, Kam Man Hui3, Gautam Sethi1,6

1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

2Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore

3Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore

4Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

5Jawaharlal Nehru Centre for Advanced Scientific Research, Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Bangalore, India

6School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia, Australia

7Department of Biological Sciences, University of North Texas, Denton, Texas, USA

8Department of Haematology-Oncology, National University Health System, Singapore

9College 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.


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