Topotecan as a molecular targeting agent which blocks the Akt and VEGF cascade in platinum-resistant ovarian cancers
Topotecan as a molecular targeting agent which blocks the Akt and VEGF cascade in platinum-resistant ovarian cancers
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DOI：
10.4161/cbt.10.11.13443
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发表时间：
2010-12
影响因子：
3.6
通讯作者：
Satoshi Tsunetoh;Y. Terai;H. Sasaki;Akiko Tanabe;Yoshimichi Tanaka;Tatsuharu Sekijima;Satoe Fujioka;Hiroshi Kawaguchi;M. Kanemura;Y. Yamashita;M. Ohmichi
中科院分区：
文献类型：
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作者：
Satoshi Tsunetoh;Y. Terai;H. Sasaki;Akiko Tanabe;Yoshimichi Tanaka;Tatsuharu Sekijima;Satoe Fujioka;Hiroshi Kawaguchi;M. Kanemura;Y. Yamashita;M. Ohmichi
（目的）拓扑替康（Topotecan）是一种新型拓扑异构酶-1（Topoisomerase-1，Topoisomerase-1，Topotecan-1）抑制剂，对铂类耐药的卵巢癌有较好的治疗作用。然而，拓扑替康治疗抑制癌细胞增殖的分子机制尚不清楚。我们研究了托泊替康是否在体外和体内增加顺铂在铂耐药卵巢癌模型中的疗效。（方法）采用顺铂耐药的Caov-3细胞和顺铂敏感的A2780细胞。采用MTS法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分析检测了顺铂和拓扑替康治疗后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卵巢癌腹腔内转移的影响。（结果）拓扑替康能显著抑制顺铂诱导的Caov-3细胞Akt活化，但对A2780细胞Akt活化无明显影响。在拓扑替康的存在下，顺铂诱导的Caov-3细胞的生长抑制和凋亡显著增强。Topotecan不仅抑制顺铂诱导的Akt活化，而且抑制VEGF和HIF-1α的表达。此外，在接种Caov-3细胞的无胸腺裸鼠中，拓扑替康治疗增加了顺铂诱导的生长抑制在腹腔内播散和腹水产生中的功效。（结论）Topotecan可抑制顺铂治疗后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类耐药卵巢癌的临床活性。这些结果为在针对铂耐药卵巢癌分子靶向药物的临床方案中使用托泊替康提供了理论基础。
(Objective) 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. (Methods) 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. (Results) 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. (Conclusion) 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.