Objective To explore the mechanism of metformin combined with letrozole in improving progesterone sensitivity of subcutaneously transplanted tumor in nude mice with human endometrial carcinoma.
Methods Forty female nude mice were randomly divided into control group and estrogen group, with 20 mice in each group. The estrogen group and the control group were randomly divided into normal saline group (intragastric administration with normal saline), medroxyprogesterone (MPA) group (intraperitoneal injection with 100 mg/kg MPA, 0.3 mL per mouse), letrozole plus MPA group (intragastric administration with 7 mg/kg letrozole, 0.1 mL per mouse, usage and dosage of MPA were the same as the MPA group), and metformin plus letrozole and MPA group (intragastric administration with 200 mg/kg metformin, 0.1 mL permouse, usage and dosage of letrozole and MPA were the same as letrozole plus MPA group), with 5 mice in each group. During the treatment, the body mass and tumor size of mice were measured regularly. After finishing the experiment, the serum sex hormones of mice were detected; the cytoma of transplanted cancer was taken out, the tumor volume was measured, and the graph of tumor growth rate was drawn to analyze the inhibitory effect of drugs on the growth of tumor cells. The expression levels of estrogen receptor (ER), progesterone receptor (PR), nuclear factor E2-related factor 2 (Nrf2) and homo sapiens longevity assurance homologue 2 (Lass2) in tumor cells were detected by immunohistochemistry.
Results In each subgroup of estrogen group and control group, the serum estrogen level of mice in the metformin plus letrozole and MPA group was significantly lower than that in the MPA group (P < 0.05). There was no significant difference in body mass in subgroups between the estrogen group and the control group (P>0.05). The inhibited rates of the growth of transplanted tumor of Ishikawa cell in the estrogen group, the MPA group, the letrozole plus MPA group, the metformin plus letrozole and MPA group were 48.25%, 67.97% and 75.43%, respectively, which were significantly higher than the 0% of normal saline group (P < 0.05). In the control group, the inhibitory rates of the MPA group, the letrozole plus MPA group, the metformin plus letrozole and MPA group on the growth of transplanted tumor of Ishikawa cell were 49.46%, 69.97% and 75.96%, respectively, which were significantly higher than the 0% of the normal saline group (P < 0.05). Immunohistochemical results showed that in the estrogen group, the expressions of Nrf2/Lass2 in the letrozole plus MPA group as well as the metformin plus letrozole and MPA group were significantly lower than that in the normal saline group (P < 0.05); in both estrogen group and control group, there was no significant difference in ER expression of transplanted tumor between subgroups with the same therapeutic method (P>0.05); in both estrogen group and the control group, the PR expressions in the letrozole plus MPA group as well as metformin plus letrozole and MPA group were significantly higher than those in the normal saline group (P < 0.05).
Conclusion Metformin plus letrozole can effectively alleviate the progesterone resistance of transplanted tumor in mice with human endometrial carcinoma, and its mechanism may be related to the down-regulation of Nrf2/Lass2 expression.
DownLoad: