NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin
Figure 6
Enhanced antitumor efficacy of the combination of hNOXA and Cisplatin In Vivo (A–D)
Tumor suppression and survival advantage in mice. A2780s cells (A, C) or SKOV3 cells (B, D) of 2×106 were inoculated subcutaneously into female nude mice at 6–8 weeks of age. Mice (five per group) were treated with PBS, pcDNA3.1, pcDNA3.1-hNOXA, Cisplatin and pcDNA3.1-hNOXA+cisplatin. In A2780s tumor model, significant differences in tumor suppression (**P<0.001) and survival time (ΔP<0.05) in mice treated with hNOXA or cisplatin versus PBS and pcDNA3.1 controls; significant difference for tumors treated with hNOXA+cisplatin versus PBS and pcDNA3.1 controls (**P<0.001; ΔΔP<0.01), and significant difference for the combination therapy versus hNOXA or cisplatin monotherapy (#P<0.05; †P<0.05). Similar results were also found in SKOV3 model, except that no significant differences in tumor suppression (P = 0.222) and survival time (P = 0.433) between cisplatin- and pcDNA3.1-treated tumors were found. (E–F) TUNEL staining of tumor tissues. Representative sections were taken from A2780s (E) and SKOV3 (F) tumor tissues of mice receiving PBS, pcDNA3.1, hNOXA, cisplatin and hNOXA+cisplatin. (G) Apoptotic index within A2780s and SKOV3 tumor tissues were counted. In A2780s model, statistically significant difference in the apoptotic index for tumors treated with hNOXA or cisplatin versus PBS and pcDNA3.1 controls (**P<0.001); significant difference for tumors treated with hNOXA+cisplatin versus the two controls (**P<0.001); and significant difference for the combination therapy versus hNOXA or cisplatin monotherapy (##P<0.001). Similar results were also found in SKOV3 model, except that no significant differences in the apoptotic index between cisplatin-treated tumor and pcDNA3.1-treated tumor (P = 0.981) or PBS-treated tumor (P = 0.705) were found. The apoptotic index was calculated as a ratio of the apoptotic cell number to the total cell number in each field. (H) RT-PCR analysis of expression of exogenous hNOXA in vivo.