Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; ABION Inc. R&D Center, 9th Floor, HanWha Biz Metro Building, 242 Digital-ro, Guro-gu, Seoul 08394, Republic of Korea.
Neoplasia. 2017 Oct;19(10):735-749. doi: 10.1016/j.neo.2017.07.005. Epub 2017 Aug 24.
Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo. Compared to the E6/E7 SP alone, E6/E7 SP with cisplatin treatment effectively restored TP53 and RB/E2F signaling and contributes to differences in cell fate, such as apoptosis or cell cycle arrest. We also developed a cellular dynamics model that includes TP53-RB/E2F dynamics and cell proliferation profiles, and confirmed its utility for investigating E6/E7 siRNA-based combination regimens. Using a dual reporter system, we further confirmed the cross talk between TP53 and RB/E2F signaling mechanisms. Treatment of E6/E7 SP cationic liposome (i.v.) with cisplatin and paclitaxel (i.p.) potentially inhibited tumor growth in BALB/c-nude mice. Altogether, our findings suggest that stabilization of TP53 and the RB/E2F repressor complex by E6/E7 SP combined with low-dose chemotherapy can effectively suppress tumor growth.
毒性和耐药性仍然是晚期或复发性宫颈癌治疗的主要挑战，因为治疗需要高剂量的化疗药物。人乳头瘤病毒（HPV）E6/E7 siRNA 恢复 TP53 和低磷酸化视网膜母细胞瘤（pRB）蛋白，使 HPV 阳性宫颈癌细胞对化疗药物敏感。在这里，我们研究了 E6/E7 siRNA 对决定细胞命运的 TP53 和 RB/E2F 信号网络动态行为的治疗效果。在体外和体内分析了 HPV E6/E7 siRNA 池（SP）与化疗药物联合对 TP53 和 RB/E2F 信号、增殖和凋亡的协同作用。与单独的 E6/E7 SP 相比，E6/E7 SP 与顺铂联合治疗可有效恢复 TP53 和 RB/E2F 信号，并导致细胞命运的差异，如凋亡或细胞周期停滞。我们还开发了一个包括 TP53-RB/E2F 动力学和细胞增殖谱的细胞动力学模型，并证实了其用于研究基于 E6/E7 siRNA 的联合方案的效用。使用双报告系统，我们进一步证实了 TP53 和 RB/E2F 信号机制之间的串扰。用顺铂和紫杉醇（i.p.）静脉注射 E6/E7 SP 阳离子脂质体（i.v.）治疗可能抑制 BALB/c 裸鼠肿瘤生长。总之，我们的研究结果表明，E6/E7 SP 与低剂量化疗联合稳定 TP53 和 RB/E2F 抑制复合物可有效抑制肿瘤生长。
