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Inhibitory effect of rapamycin combined with cisplatin on growth of human cervical carcinoma HeLa cell subcutaneous xenografts in nude mice and the mechanisms
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Abstract:
Objective: To evaluate the effect of rapamycin (RAPA) and cisplatin (DDP) used alone or in combination on the growth of human cervical carcinoma HeLa cell subcutaneous xenografts in nude mice and the possible mechanisms. Methods: Nude mice were subcutaneously inoculated with HeLa cells to establish a subcutaneous transplantation tumor model of cervical cancer. Mice were randomly divided into a control group, RAPA group, DDP group, and RAPA+DDP group. The tumor weight and volume were observed during therapeutic process. The mRNA and protein expressions of hypoxia-inducible factor-1alpha ( HIF-1α ) and vascular endothelial growth factor (VEGF) were detected by RT-PCR, immunohistochemistry and Western blotting. Results: Compared with the RAPA group, the tumor weight (\[0.42±0.04\] vs \[0.53±0.03\]g, P<0.05) and the tumor volume (\[568.70±36.12\] vs \[797.81±111.98\] mm3, P<0.01) were significantly reduced in the RAPA+DDP group. Moreover, in comparison with the DDP group, the tumor weight (\[0.42±0.04\] vs \[0.52±0.04\]g, P<0.05) and the tumor volume (\[568.70±36.12\] vs \[766.16±132.27\]mm3, P<0.01) were significantly reduced in the RAPA+DDP group. RT-PCR and Western blotting results showed that the expression of HIF-1α mRNA in transplanted tumors was down-regulated in the RAPA+DDP group compared with the RAPA and DDP groups (\[31.215±0.706\] vs \[50.58±1.25\], \[48.63±1.56\]，P<0.05), and the expression of HIF-1α protein was also down-regulated (\[38.07±0.09\] vs \[55.69±3.60\], \[59.50±1.54\], P<0.05). Moreover, the expression of VEGF mRNA in transplanted tumors was significantly decreased in the RAPA+DDP group compared with the RAPA and the DDP groups (\[46.64±0.60\] vs \[62.20±0.62\], \[61.64±1.21\], P<0.05), and decreased VEGF protein expression can be shown in the RAPA+DDP group (\[119.28±2.69\] vs \[150.31±4.77\], \[153.84±3.39\], P<0.05). Immunohistochemistry showed that the AOD value of HIF-1α in transplanted tumors was decreased in the RAPA+DDP group compared with the RAPA and the DDP groups (\[0.37±0.03\] vs \[0.57±0.06\], \[0.55±006\]，P<0.05), and decreased AOD value of VEGF can also be shown in the RAPA+DDP group (\[0.48±0.03\] vs \[0.62±0.04\], \[0.61±0.07\], P<0.05). Conclusion: RAPA combined with DDP shows an inhibitory effect on growth of human cervical carcinoma HeLa cell subcutaneous xenografts. The possible underlying mechanism is related to the down-regulation of HIF-1α and VEGF expressions.
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Project Supported:
Project supported by the Social Development Foundation of Dalian Science and Technology Bureau (No. 2008E13SF195)
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