Abstract:

Objective To study the inhibition of growth and induction of differentiation of mouse B16 melanoma by acitretin and their mechanism. Methods Animal models of B16 melanoma were established by subcutaneously inoculation of cultured B16 cells into the right axilla of mice. All mice were divided into 5 groups, negative control group treated with peanut oil, low-dose acitretin group treated with acitretin 10 mg per kilogram of body weight per day, high-dose acitretin group treated with 20 mg per kilogram body weight per day, cisplatin group treated with cisplatin 10 mg per kilogram body weight, combination group treated with acitretin 20 mg per kilogram body weight per day plus cisplatin 10 mg per kilogram body weight. Acitretin was given daily via intragastric administration, and cisplatin was given with an interval of 7 days, from day 2 till day 22 after the inoculation. The growth of transplanted tumor was measured with an interval of 3 days. After drug withdrawal, mice were killed, transplanted tumors were obtained for the measurement of tumor weight, pathological examination and immunohistochemical staining for survivin, Fas and vascular endothelial growth factor （VEGF）. Results Acitretin could significantly inhibit the growth of B16 melanoma, the average weight and volume of transplanted tumor in the treated groups were significantly lower than those in the negative control group （all P < 0.01）. Pathological examination revealed that in the control group, tumor cells showed typical heteromorphism, and closely arranged with an obscure boundary, whereas in the treated groups, a massive or focal necrosis at different levels was observed in the center and margin of tumor tissue. The relative expression levels of suvivin, VEGF and Fas protein were 3.600 ± 0.966, 4.600 ± 0.966, 4.300 ± 0.949 respectively, in high-dose acitretin group, 2.100 ± 0.568, 2.400 ± 0.516, 5.900 ± 0.730 respectively, in combination group, 5.900 ± 1.370, 6.100 ± 1.197, 2.100 ± 0.568, respectively, in the negative control group, and a significant decrease was observed in the expression of suvivin and VEGF in the former two groups along with an increase in Fas expression compared with the negative control group （all P < 0.01). Additionally, in all the treated mice, the expression of survivin was negatively correlated to that of Fas （rs = -0.77, P < 0.01), but positively to that of VEGF （rs = 0.72, P < 0.01）. Conclusions Acitretin can obviously inhibit the growth and induce the differentiation of B16 melanoma, which may be associated with its downregulation of survivin and VEGF expression as well as the upregulation of Fas expression.

Key words: Acitretin;malignant melanoma;CDDP;Survivin;Fas;VEGF