Liu Lili, Gou Maling, Yi Tao, Bai Yu, Wei Yuquan, Zhao Xia
Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Oncol Rep. 2014 Apr;31(4):1623-8. doi: 10.3892/or.2014.2995. Epub 2014 Jan 24.
Cisplatin is normally administered in chemotherapy for ovarian cancer, but is accompanied by severe dose-dependent toxicity. The combination of cisplatin with other antitumor agents may be a useful alternative for achieving higher antitumor efficiency and lower toxicity. Claudin-3 (CLDN3), a commonly upregulated gene in 90% of ovarian cancers, has been identified as a novel therapeutic target of ovarian cancer. Therefore, in the present study, we constructed a recombinant plasmid carrying an shRNA targeting CLDN3 (pshCLDN3), and investigated the antitumor effects of the combination therapy of pshCLDN3 and a low-dose of cisplatin for the treatment of ovarian cancer. Heparin-polyethyleneimine (HPEI) nanogel, a novel gene carrier with superior biodegradability, excellent blood compatibility and low-toxicity, was used to deliver pshCLDN3 into ovarian cancer cells. The knockdown efficiency was determined by western blot analysis and CLDN3 immunostaining. Nude mice bearing intraperitoneal ovarian carcinomas were treated with pshCLDN3/HPEI complexes, low-dose cisplatin, pshCLDN3/HPEI plus low-dose cisplatin or control agents, respectively. The results showed that pshCLDN3/HPEI effectively suppressed the expression of CLDN3 in ovarian cancer. The combination therapy of pshCLDN3/HPEI and low-dose cisplatin exhibited enhanced antitumor activity, when compared with either agent alone, as evidenced by mean tumor weight analysis, Ki-67 immunostaining analysis and TUNEL assay, without obvious systemic toxicity. These results indicate that pshCLDN3/HPEI combined with low-dose cisplatin demonstrates apparent synergistic antitumor activity without marked toxicity. Our study offers a novel therapeutic strategy for the treatment of ovarian cancer.
顺铂通常用于卵巢癌的化疗，但会伴有严重的剂量依赖性毒性。顺铂与其他抗肿瘤药物联合使用可能是提高抗肿瘤效率和降低毒性的有效替代方案。Claudin-3（CLDN3）是90%的卵巢癌中常见的上调基因，已被确定为卵巢癌的一个新的治疗靶点。因此，在本研究中，我们构建了携带靶向CLDN3的短发夹RNA（pshCLDN3）的重组质粒，并研究了pshCLDN3与低剂量顺铂联合治疗卵巢癌的抗肿瘤作用。肝素-聚乙烯亚胺（HPEI）纳米凝胶是一种新型基因载体，具有优异的生物降解性、良好的血液相容性和低毒性，用于将pshCLDN3递送至卵巢癌细胞。通过蛋白质免疫印迹分析和CLDN3免疫染色确定敲低效率。分别用pshCLDN3/HPEI复合物、低剂量顺铂、pshCLDN3/HPEI加低剂量顺铂或对照剂治疗携带腹腔内卵巢癌的裸鼠。结果表明，pshCLDN3/HPEI能有效抑制卵巢癌中CLDN3的表达。与单独使用任何一种药物相比，pshCLDN3/HPEI与低剂量顺铂联合治疗表现出增强的抗肿瘤活性，平均肿瘤重量分析﹑Ki-67免疫染色分析和TUNEL检测均证明了这一点，且无明显的全身毒性。这些结果表明，pshCLDN3/HPEI与低剂量顺铂联合具有明显的协同抗肿瘤活性且无明显毒性。我们的研究为卵巢癌的治疗提供了一种新的治疗策略。
