| Background and objective:Despite a decline in incidence, gastric cancer remains one of the leading causes of cancer-related deaths worldwide. Surgery remains the mainstay of any curative treatment; however, approximately two-thirds of patients diagnosed with gastric cancer have unresectable locally advanced and/or metastatic disease. The 5-year survival rate of patients with advanced loco-regional gastric cancer who have undergone adjuvant chemotherapy after curative resection remains low because of the high risk of local recurrence. A perspective randomized Intergroup (INT)-0116 trial (556 patients) demonstrated reduction in local recurrence rate by postoperative regional radiation plus chemotherapy and better survival in the adjuvant arm. Radiotherapy is the main locoregional control modality for unresectable gastric cancer. The National Comprehensive Cancer Network guidelines recommend radiotherapy as a standard treatment for gastric cancer patients with a high risk of recurrence. However, there are two major limitations in the treatment of gastric cancer with radiation:intrinsic or acquired resistance to radiotherapy and nonspecific toxicity towards gastric mucosa and surrounding healthy tissues.Radiosensitizer can enhance the radiation effects of local control rate due to the property of increasing the sensitivity of tumor cells to radiation. It is a very promising way to search an effective radiosensitizer from herbs which have the superiority of low toxicity and high safety. In our lab, we identified the active effective monomer, ursolic acid, which had a valid anti-tumor activity and synergistic sensitizing effects in combination with docetaxel in vitro and in vivo. However, whether ursolic acid can enhance the radiation effects in malignant neoplasm has not been reported at home and aboard. The experiment was to explore the effects and possible mechanism in vitro of radiosensitization by ursolic acid in BGC-823 cell line from human adenocarcinoma gastric cancer to supply the theory support for the clinical use.Materials and Methods:The aim of the current study was to clarify the effect of a widely studied chemopreventive agent, ursolic acid on radiation sensitivity in BGC-823 cell line.1. The effects of ursolic acid on BGC-823 cells were determined by the MTT assay.2. Suitable concentration of ursolic acid for BGC-823 cells was screened by the MTT assay, and radiosensitivity was determined by clonogenic survival assay.3. The effects of ursolic acid with radiation on the cell-cycle distribution, apoptosis, the production of reactive oxygen species and marker of cell proliferation, Ki-67 protein, were examined.Results:1. MTT experimental results showed that ursolic acid was cytotoxic to BGC-823 cells in a concentration-dependent manner. The quarter-maximal inhibitory concentration values was 10.5 ±1.15ug/ml.2. Pretreatment of UA 10μg/ml for 24h on BGC-823 cells enhanced the radiosensitivity of BGC-823 cells. The sensitization enhancement radio=1.315.3. A combination of radiation and ursolic acid significantly increased the apoptotic rate in BGC-823 cells compared with radiation alone (78.2%; 12.5%). The percentage of cells in G1 phase and G2/M phase with radiation in combination with ursolic acid were increased compared with radiation alone (G1 phase:60.28%; 51.87%, G2/M phase:13.67%; 3.14%), and the percentage of cells in S phase was decreased from 44.99% to 26.04%. The combination of radiation and ursolic acid caused a significant increase in the production of reactive oxygen species, the mean fluorescence intensity of DCF was improved from 14227 to 20586 (P<0.01). The Ki-67 proliferation index of the combination group was decreased compared with radiation alone (Ki-67 positive rate:69.6%±2%; 81.4%±2%,p<0.01).Conclusion:Collectively, our results suggest that ursolic acid might be useful as a radiation sensitizer to treat some types of gastric carcinoma. The sensitization mechanism may be relevant to the redistribution of cell-cycle, increasing the apoptotic rate and the production of intracellular reactive oxygen species and downregulating the Ki-67 proliferation index. |
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