Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan.
Cancer Biol Ther. 2010 Dec 1;10(11):1137-46. doi: 10.4161/cbt.10.11.13443.
Topotecan, a novel topoisomerase-1 inhibitor, is a drug that appears to be effective against platinum-resistant ovarian cancers. However, the molecular mechanisms by which Topotecan treatment inhibits cancer cell proliferation are unclear. We investigated whether Topotecan increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo.
We used Cisplatin-resistant Caov-3 cells and Cisplatin-sensitive A2780 cells. We examined the effect of Cisplatin and Topotecan on the cell viability of Caov-3 and A2780 cells by MTS assay. We examined the Akt kinase activity, VEGF and HIF-1α expression after Cisplatin and Topotecan by a Western blot analysis. Moreover, we also evaluated the effects of Cisplatin and Topotecan on the intraabdominal dissemination of ovarian cancer in vivo.
Topotecan significantly inhibited Cisplatin-induced Akt activation in Caov-3 cells, but not in A2780 cells. In the presence of Topotecan, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in Caov-3 cells. Topotecan inhibited not only Cisplatin-induced Akt activation but also VEGF and HIF-1α expression. Moreover, treatment with Topotecan increased the efficacy of Cisplatin-induced growth inhibition in the intraabdominal dissemination and production of ascites in athymic nude mice inoculated with Caov-3 cells.
We herein demonstrated that Topotecan inhibits Akt kinase activity and VEGF transcriptional activation after Cisplatin treatment in platinum-resistant ovarian cancers. We clarified how Topotecan enhanced the clinical activity in the platinum-resistant ovarian cancer. These results provide a rationale for using Topotecan in clinical regimens aimed at molecular targeting agents in platinum-resistant ovarian cancers.
拓扑替康是一种新型拓扑异构酶-1 抑制剂，似乎对铂耐药卵巢癌有效。然而，拓扑替康治疗抑制癌细胞增殖的分子机制尚不清楚。我们研究了拓扑替康是否能提高铂耐药卵巢癌模型中顺铂的疗效。
我们使用了铂耐药的 Caov-3 细胞和顺铂敏感的 A2780 细胞。我们通过 MTS 分析检测顺铂和拓扑替康对 Caov-3 和 A2780 细胞活力的影响。我们通过 Western blot 分析检测顺铂和拓扑替康处理后 Akt 激酶活性、VEGF 和 HIF-1α 的表达。此外，我们还评估了顺铂和拓扑替康对体内卵巢癌腹腔播散的影响。
拓扑替康显著抑制了顺铂诱导的 Caov-3 细胞中的 Akt 激活，但对 A2780 细胞没有影响。在拓扑替康存在的情况下，顺铂诱导的 Caov-3 细胞生长抑制和凋亡明显增强。拓扑替康不仅抑制了顺铂诱导的 Akt 激活，还抑制了 VEGF 和 HIF-1α 的表达。此外，用拓扑替康治疗增加了顺铂诱导的生长抑制在荷瘤裸鼠腹腔播散和腹水产生的疗效。
我们在此证明，拓扑替康抑制铂耐药卵巢癌中顺铂处理后 Akt 激酶活性和 VEGF 的转录激活。我们阐明了拓扑替康如何增强铂耐药卵巢癌的临床疗效。这些结果为在铂耐药卵巢癌的分子靶向治疗方案中使用拓扑替康提供了依据。
