Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo |
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| Institution: | 1. Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India;2. Division of Bacteriology and Mycology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India;3. Division of Animal Biotechnology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India;4. Division of Pathology, Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P. 243 122, India;1. Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India;2. Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India;3. Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India;1. Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;2. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India;3. Academy of Scientific and Innovative Research (AcSIR), CSIR-IIIM Campus, Jammu, India;1. Faculty of Applied Sciences, UCSI University, 56000 Cheras, Kuala Lumpur, Malaysia;2. School of Science, Monash University Sunway, 46150 Petaling Jaya, Selangor, Malaysia;3. Xiamen University Malaysia, Bandar Sunsuria, 43900 Sepang, Selangor, Malaysia;1. State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China;2. Department of Physiology, School of Medicine, Wuhan University, Wuhan, 430071, PR China;3. Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan, 430071, PR China;4. Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China;5. College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China |
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| Abstract: | 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 unclear. 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 expression 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. |
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| Keywords: | Apoptosis Betulinic acid Invasion Migration Colorectal cancer cells |
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