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    Contents lists available at ScienceDirect
    Bioorganic & Medicinal Chemistry
    journal homepage: www.elsevier.com/locate/bmc
    Betulinic acid induces apoptosis and inhibits metastasis of human colorectal T cancer cells in vitro and in vivo
    Anqi Zeng1, Hua Hua1, Li Liu, Junning Zhao
    Institute of Translational Pharmacology and Clinical Application of Sichuan Academy of Chinese Medicine Sciences, Sichuan Center for Translational Medicine of Traditional Chinese Medicine, Sichuan Engineering Technology Research Center of Genuine Regional Drug, Biological Assay Key Laboratory of State Administration of Traditional Chinese Medicine for TCM Quality, Sichuan Provincial Key Laboratory of Quality Evaluation and New Drug Creation of Traditional Chinese Medicine, Chengdu, Sichuan 610041, China
    Keywords:
    Apoptosis
    Betulinic acid
    Invasion
    Migration
    Colorectal cancer cells 
    Betulinic acid (BA) is a pentacyclic triterpenoids extracted from birch with a wide range of biological properties. Recent studies have shown that BA has significant cytotoxicity to various types of human cancer cells, and shows potential in cancer treatment. However, the efficacy of BA on human colorectal cancer tumor cells is still un-clear. The purpose of our study was to evaluate the anti-cancer activity of BA in human colorectal cancer cells in vitro and in vivo to investigate the possible mechanism. In this experiment, we found that BA inhibited colorectal cancer cell lines in vitro with a time-dependent and dose-dependent manner. Moreover, BA could induce cell apoptosis by upregulating expression of Bax and cleaved caspase-3 and downregulating protein of Bcl-2. BA could increase the production of reactive oxygen species and reduce mitochondrial membrane potential of cancer cell, suggesting that BA induced cancer cells apoptosis by mitochondrial mediated pathways. Furthermore, BA significantly inhibited the migration and invasion of colorectal cancer cells, reduced the ex-pression of matrix metalloproteinase (MMPs) and increased the expression of MMPs inhibitor (TIMP-2). In addition, the growth of tumor was significantly suppressed by intraperitoneal administration of 20 mg/kg/day of BA in a xenograft tumor mouse model of HCT-116. Histopathological and immunohistochemical analysis showed that MMP-2+ cells and Ki-67+ cells were reduced and cleaved caspase-3+ cells were increased in tumor tissues of mice after BA administration. The results showed that BA not only promoted the apoptosis of colorectal cancer cells, but also inhibited the metastasis of cancer cells. Our results suggest that BA can be a potential natural drug to inhibit the growth and metastasis of colorectal cancer.