Metformin incombination with curcumin inhibits the growth, metastasis, and angiogenesis of hepatocellular carcinoma in vitro and in vivo

• Published in: Molecular carcinogenesis 2018-01, Vol.57 (1), p.44-56
• Main Authors: Zhang, Hui‐Hui, Zhang, Ying, Cheng, Yan‐Na, Gong, Fu‐Lian, Cao, Zhan‐Qi, Yu, Lu‐Gang, Guo, Xiu‐Li
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Animals; Antidiabetics; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell Line; Cell Proliferation - drug effects; Cells, Cultured; Curcumin; Curcumin - administration & dosage; Diabetes mellitus; Epidermal growth factor receptors; Female; Gelatinase A; HCC; Hep G2 Cells; Hepatocellular carcinoma; Hepatoma; Humans; Liver cancer; Liver Neoplasms - blood supply; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Metastases; Metastasis; Metformin; Metformin - administration & dosage; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Neoplasm Metastasis; Neovascularization, Pathologic - prevention & control; NF-κB protein; p53 Protein; PTEN protein; Rodents; Signal Transduction - drug effects; Stat3 protein; TOR protein; Tumor Burden - drug effects; Tumor cells; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22718

Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti‐diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co‐treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR‐2, up‐regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF‐κB and EGFR/STAT3 signaling. Co‐administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti‐tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment.