A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma.
Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development.
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Bo
B
Hu
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Soochow University, Suzhou, 215004, PR China.
Ding
D
Sun
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Chao
C
Sun
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Yun-Fan
YF
Sun
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Hai-Xiang
HX
Sun
The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205, USA; Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
Qing-Feng
QF
Zhu
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Xin-Rong
XR
Yang
Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
Ya-Bo
YB
Gao
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
Wei-Guo
WG
Tang
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China; Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China.
Jia
J
Fan
The Sol Goldman Pancreatic Cancer Research Center, Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Anirban
A
Maitra
The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD, 21205, USA. Electronic address: rander54@jhmi.edu.
Robert A
RA
Anders
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China. Electronic address: drxuyang@gmail.com.
Yang
Y
Xu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage / Q000737:chemistry; D004058:Diffusion; D004357:Drug Synergism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D000077157:Sorafenib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D053769:Nanocapsules; D010671:Phenylurea Compounds; D011108:Polymers; D009536:Niacinamide; D000077157:Sorafenib; D003474:Curcumin
Curcumin; Hepatocellular carcinoma; MMP-9; NF-κB; Sorafenib