The phosphorylation levels of Akt the total protein levels of Akt

A2780 cells by MTS analysis and we examined the effect of Cisplatin and Topotecan Dub inhibitor on the cell viability of Caov 3. We examined the Akt kinase exercise, VEGF and HIF 1 expression after Cisplatin and Topotecan with a western blot analysis. More over, we also examined the consequences of Cisplatin and Topotecan to the intra-abdominal dissemination of ovarian cancer in vivo. We herein demonstrated that Topotecan inhibits Akt kinase activity and VEGF transcriptional activation after Cisplatin therapy in platinum resistant ovarian cancers. We responded how Topotecan enhanced the medical activity in the platinum resistant ovarian cancer. These give a reason for applying Topotecan in clinical regimens targeted at molecular targeting agents in platinum resistant ovarian cancers. We have previously reported that Akt inactivation sensitizes human ovarian cancer cells to Cisplatin and Paclitaxel. Consequently, inhibition of antiapoptotic Meristem signals, including these medicated by the Akt pathway, has been proposed as a promising strategy to enhance the efficacy of conventional chemotherapeutic agents. Inhibition of this cascade applying gene transfection was effective in avoiding Cisplatin resistance, since the PI3/Aktcascade is involved with Cisplatin resistance. Tumor cells secrete vascular endothelial growth factor, which advances the proliferation of endothelial cells resulting in subsequent tumor progression and tumor angiogenesis. Environmental stresses, for example chemotherapy upregulate HIF 1 and VEGF signaling in cancer cells, thus leading to enhanced tumorigenic and angiogenic potential. Among the numerous Akt substrates, the target of rapamycin is mainly implicated in the regulation of HIF 1 protein at the translocation level. Thus, the inhibition of the VEGF stream may well be more efficient for blocking Cisplatin resistance. Nevertheless, little molecular agents which prevent the Akt and/or VEGF cascade have not yet been found. Topotec an camptothecin, a water-soluble Foretinib camptothecin analog, is a novel topoisomerase I inhibitor that is active against numerous human tumor cell lines and xenograft tumors. Topotecan has additionally demonstrated clinical activity in ovarian carcinoma, small cell and non small cell bronchogenic carcinomas and myeloid leukemia. Lately, Phase II trial showed that Topotecan is beneficial in both platinum vulnerable and platinum immune ovarian cancers. Pre-clinical models have demonstrated that Topotecan can improve platinum mediated cytotoxicity through inhibition of DNA repair. Furthermore, it was reported that Topotecan induces apoptosis in human lung cancer cells, simply, by downregulating the PI3K Akt signaling pathway. These considerations led us to examine whether Topotecan inhibits the PI3K/Akt signaling pathway in ovarian cancers. Furthermore, we evaluated thus whether Topotecan inhibits HIF 1 protein accumulation by down-regulation of the PI3k/ Akt mTOR pathway in Cisplatin immune ovarian cancers.