Research Article: Investigating Effect of Rapamycin and Metformin on Angiogenesis in Hepatocellular Carcinoma Cell Line

Date Published: March 18, 2018

Publisher: Tabriz University of Medical Sciences

Author(s): Mandana Rastegar, Haji-Amin Marjani, Yaghoub Yazdani, Majid Shahbazi, Masoud Golalipour, Touraj Farazmandfar.


Purpose: Human hepatocellular carcinoma is one of the most common causes of death in the world. Metformin and rapamycin may decrease the expression of VEGF protein and subsequently angiogenesis. The purpose of this study was to evaluate the effect of these two drugs on expression of VEGF protein and the cell proliferation in the hepatocellular carcinoma cell line (ATCC HB-8065).

Partial Text

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and is the fourth leading cause of cancer-related death in the world.1 HCC is seventh most common cancer in men and the ninth in women.2 However, the increased prevalence of HCC in communities with a high risk, in men is higher than women.3 HCC is an aggressive malignancy with poor prognosis. Current chemotherapeutic drugs are not effective to control tumor growth and drug resistance is a common problem in a successful therapy. Therefore, novel approaches in chemotherapy may be needed to improve the survival rate in patients with HCC.4 The treatment with anti-angiogenic agents may be a promising approach to treat HCC. Angiogenesis is a complex process that is based on cooperation between various cells, such as pericytes, endothelial cells, fibroblasts and smooth muscle cells.‏ These cells produce a variety of cytokines and growth factors that interact with other cells or with the extracellular matrix and affect migration, proliferation and angiogenesis.5 Angiogenesis plays a key role in tumor growth, progression and metastasis. This uncontrolled growth is well established in many tumors such as ovarian,6 lung,7 colon,8 prostate,9 brain10 and lymphoid11 tumors. Inhibition of angiogenesis may be a valuable method for controlling cancer. Without angiogenesis, tumor growth potentially is limited due to lack of blood flow and proliferation factors. Metastatic potential of tumors develops through the increased angiogenesis. This process was performed by disrupting the balance between of pro-angiogenic and anti-angiogenic factors via increasing the presence of pro-angiogenic factors such as VEGF.12 Some studies on angiogenesis inhibitors in animal models showed that angiogenesis inhibition can destroy many types of tumors.13 Two strategies used in the development of anti-angiogenic agents include exogenous angiogenic inhibitors such as monoclonal antibody against VEGF, and endogenous inhibitors such as endostatin and angiostatin.14

The differential effect of metformin and rapamycin on VEGF expression calls into question the use of mTOR inhibitors to target angiogenesis. Further analysis of the molecular pathways affected by both drugs may lead the authors to define new therapeutic strategies. This information may help to design a combination treatment to increase the efficacy of metformin and rapamycin in HCC.

This work was supported by the research department in Golestan University of Medical Sciences, Gorgan, Iran (Grant number 930705044).

Not applicable.

The authors declare no conflict of interests.




Leave a Reply

Your email address will not be published.