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  • br Introduction br Cancer is still

    2020-08-18


    1. Introduction
    Cancer is still a serious disease in today's world, and the annual morbidity and mortality rate remain high in the world. Studies have shown that colorectal cancer is a malignant tumor with a very high mortality.1 Although tumor treatment methods tend to be diversified in recent years and the treatment methods develop rapidly, chemotherapy is still an important treatment method for malignant tumors, especially colorectal cancer, clinically. However, there are many defects in the treatment methods of chemotherapy, such as low specificity and large toxic and side effects.2
    Natural products have been used to treat human diseases for thousands of years and are of great significance and value in the discovery and development of new drugs.3,4 At present, most anti-tumor and anti-infection drugs on the market come from natural
    Corresponding author.
    1 These authors contributed equally to this work. 
    products.5 Natural products have many excellent properties, in-cluding high efficiency and low toxicity.6 In order to reduce the toxic and side effects of therapeutic drugs and improve the quality of life of patients, in recent years, searching for low-toxic and high-efficiency anti-tumor drugs has become the common goal of scientists and doctors. Therefore, the identification of natural plant compounds from medicinal plants and natural products to fight diseases has be-come the trend of new drug development.7 Betulinic 18α-Glycyrrhetinic acid is a pen-tacyclic triterpenoid extracted from birch. Its plant sources include
    various bark extractants, acuminatissima leaves, and wild date seeds.4,8,9 Studies have shown that BA has anti-tumor, antiviral and anti-inflammatory activities, among which it is known for its anti-cancer activity.10–12 Moreover, BA could suppress tumorigenesis in various types of cancer, including breast, lung, colon, pancreatic, and prostate cancer.13–17
    Fig. 1. Antiproliferation efficacy of BA inhuman colorectal cells. (A) Proliferation ofHCT116, SW480, DLD-1 cells treated with various concentrations (0–80 μM) of BA for 48 h and 72 h. Cell viability was evaluated by MTT assay. Data represent mean ± SD at least from 3 independent experiments. (B) The effects of BA (0–20 μM) on colony formation in HCT116, SW480, DLD-1 cell lines for 12 days, the statistic results of colony formation assays presented surviving colonies. Data are expressed as
    Our results showed that BA significantly inhibited the proliferation, apoptosis, migration and invasion of colorectal cancer cells in vitro. The results of in vivo experiments were consistent with those of in vitro experiments. Our data show the anti-tumor potential of BA in human colorectal cancer cells.
    2. Results
    2.1. Anti-proliferation efficacy of BA inhuman colorectal cells
    To investigate the potential pharmacological effects of BA on human colorectal cancer cells, Firstly, we evaluated the cytotoxicity of BA by exposing colorectal cancer cells to different concentrations (0, 5, 10, 20, 40, 80 μg/mL) for 48 and 72 h. As evident from Fig. 1A, BA gradually inhibited HCT116, SW480 and DLD-1 cell proliferation and the prolonging of exposure duration. These data indicate that BA may suppress colorectal cancer cells proliferation in a con-centration‐dependent and time‐dependent manner. Then, to further explore whether BA could repress colorectal cancer cells proliferation, colony-formation assays were performed to visualize the anti pro-liferation effect of BA on HCT116, SW480 and DLD-1cells. As shown in Fig. 1B, clonogenic ability of HCT116, SW480 and DLD-1cells was in-hibited after exposure to BA. Taken together, our findings suggested that BA exerts cytostatic and cytotoxic effects on colorectal cancer cells.
    2.2. BA elicits apoptosis inhuman colorectal cells
    To explore whether BA induces colorectal cancer cells apoptosis, FCM was carried out to quantitatively evaluate it. As presented in Fig. 2A, B treatment of HCT116 cells with various concentrations of BA resulted in a dose‐dependent increase in apoptotic cells. With a view to further verifying the proapoptotic effect of BA on colorectal cancer cells, we analyzed the expression patterns of some apoptosis‐related proteins in cells by Western blot analysis after treatment with different concentrations of BA for 48 h. As exhibited in Fig. 2C, compared with untreated cells, a concentration-dependent decrease in the expression levels of Bcl-2 was observed in HCT116 cells treated with BA. In ad-dition, BA treatment also led to a dose-dependent increase in the 
    expression levels of Bax and cleaved caspase‐3 in HCT116 cells. Col-lectively, these results suggested that BA triggers colorectal cancer cells apoptosis.
    2.3. BA induces apoptosis through mitochondria-mediated apoptotic pathway inhuman colorectal cells