Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer.
Gemcitabine as a molecular targeting agent that blocks the Akt cascade in platinum-resistant ovarian cancer.
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DOI：
10.1186/1757-2215-7-38
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发表时间：
2014-04-09
影响因子：
4
通讯作者：
Ohmichi M
中科院分区：
文献类型：
--
作者：
Kawaguchi H;Terai Y;Tanabe A;Sasaki H;Takai M;Fujiwara S;Ashihara K;Tanaka Y;Tanaka T;Tsunetoh S;Kanemura M;Ohmichi M
吉西他滨（2′，2′ -二氟脱氧胞苷）是对复发性、铂类耐药卵巢癌表现出活性的许多非铂类药物之一。然而，吉西他滨治疗抑制铂耐药卵巢癌细胞增殖的分子机制仍不清楚。我们研究了吉西他滨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。我们使用顺铂抗性Caov-3细胞、A2780 CP细胞和顺铂敏感性A2780细胞，使用3-（4，5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺基苯基）-2H-四唑（MTS）测定来检查顺铂和吉西他滨的细胞活力的敏感性，以及使用Matrigel的侵袭测定来检查顺铂和吉西他滨的侵袭活性的敏感性。我们研究Akt激酶活性和基质金属蛋白酶9（MMP 9）表达顺铂和吉西他滨治疗后，使用Western印迹分析和血管内皮生长因子（VEGF）的mRNA表达，使用半定量RT-PCR。此外，我们评估了顺铂和吉西他滨在体内对卵巢癌腹腔内转移的影响。吉西他滨在Caov-3和A2780 CP细胞中显著抑制顺铂诱导的Akt活化，但在A2780细胞中不抑制。在吉西他滨的存在下，顺铂诱导的Caov-3和A2780 CP细胞的生长抑制和凋亡显著增强。顺铂和吉西他滨的共同治疗几乎完全抑制了两种类型的细胞通过基质胶的侵袭;然而，单独的顺铂和吉西他滨都不能抑制两种类型的细胞的侵袭。吉西他滨不仅能抑制顺铂诱导的Akt活化，还能抑制MMP 9和VEGF mRNA的表达。此外，吉西他滨治疗增加了顺铂诱导的生长抑制的腹腔内传播和腹水在接种Caov-3细胞的无胸腺裸鼠中的产生的功效。我们在此证明，吉西他滨抑制Akt激酶活性和血管生成活性后，顺铂治疗铂耐药的卵巢癌细胞。这些结果为在含有分子靶向剂的临床方案中使用吉西他滨治疗铂耐药卵巢癌提供了理论依据。
Gemcitabine (2′, 2′ –difluorodeoxycytidine) is one of many nonplatinum drugs that exhibit activity in recurrent, platinum-resistant ovarian cancer. However, the molecular mechanisms by which Gemcitabine treatment inhibits the proliferation of platinum-resistant ovarian cancer cells still remain unclear. We investigated whether Gemcitabine increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo. We used Cisplatin-resistant Caov-3 cells, A2780CP cells and Cisplatin-sensitive A2780 cells to examine the sensitivity of the cell viability of Cisplatin and Gemcitabine using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and the sensitivity of the invasive activity of Cisplatin and Gemcitabine using an invasion assay with Matrigel. We examined the Akt kinase activity and matrix metalloproteinase 9 (MMP9) expression following Cisplatin and Gemcitabine treatment using a Western blot analysis and the mRNA expression of vascular endothelial growth factor (VEGF) using semi-quantitative RT-PCR. Moreover, we evaluated the effects of Cisplatin and Gemcitabine on the intra-abdominal dissemination of ovarian cancer in vivo. Gemcitabine significantly inhibited Cisplatin-induced Akt activation in the Caov-3 and A2780CP cells, but not in the A2780 cells. In the presence of Gemcitabine, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in the Caov-3 and A2780CP cells. Co-treatment with Cisplatin and Gemcitabine almost completely inhibited invasion of both types of cells through the Matrigel; however, neither Cisplatin nor Gemcitabine alone inhibited the invasion of both types of cells. Gemcitabine inhibited not only the Cisplatin-induced activation of Akt, but also the MMP9 and mRNA expression of VEGF. Moreover, treatment with Gemcitabine increased the efficacy of Cisplatin-induced growth inhibition of the intra-abdominal dissemination and production of ascites in the athymic nude mice inoculated with Caov-3 cells. We herein demonstrated that Gemcitabine inhibits the Akt kinase activity and angiogenetic activity following treatment with Cisplatin in platinum-resistant ovarian cancer cells. These results provide a rationale for using Gemcitabine in clinical regimens containing molecular targeting agents against platinum-resistant ovarian cancers.
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影响因子：
3.6
作者：
Tanaka Y;Terai Y;Kawaguchi H;Fujiwara S;Yoo S;Tsunetoh S;Takai M;Kanemura M;Tanabe A;Ohmichi M
通讯作者：
Ohmichi M
影响因子：
4.7
作者：
SAKURAGI, N;NISHIYA, M;FUJIMOTO, S
通讯作者：
FUJIMOTO, S
影响因子：
8
作者：
Grooteclaes, ML;Frisch, SM
通讯作者：
Frisch, SM
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
7.5
作者：
Takeichi, Masatoshi
通讯作者：
Takeichi, Masatoshi