PIK Akt signaling regulates cell survival apoptosis

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 action, VEGF and HIF 1 expression after Cisplatin and Topotecan by a western blot analysis. Moreover, we also examined Bortezomib the results of Topotecan and Cisplatin about the intraabdominal dissemination of ovarian cancer in vivo. We herein demonstrated that Topotecan inhibits VEGF transcriptional activation and Akt kinase activity after Cisplatin treatment in platinum resistant ovarian cancers. We clarified how Topotecan enhanced the scientific activity in the platinum resistant ovarian cancer. These give a reason for applying Topotecan in clinical regimens targeted at molecular targeting brokers in platinum resistant ovarian cancers. We've previously reported that Akt inactivation sensitizes human ovarian cancer cells to Cisplatin and Paclitaxel. Consequently, inhibition Cellular differentiation of antiapoptotic indicators, such as those medicated by the Akt pathway, is proposed as a promising strategy to enhance the efficacy of conventional chemotherapeutic agents. Inhibition of the cascade using gene transfection was effective in avoiding Cisplatin resistance, since the PI3/Aktcascade is involved in Cisplatin resistance. Tumor cells secrete vascular endothelial growth factor, which escalates the proliferation of endothelial cells resulting in subsequent tumor progression and tumor angiogenesis. Environmental stresses, such as chemotherapy upregulate HIF 1 and VEGF signaling in cancer cells, thus leading to improved tumorigenic and angiogenic potential. Among the numerous Akt substrates, the target of rapamycin is mainly implicated in the regulation of HIF 1 protein in the translocation level. Therefore, the inhibition of the VEGF cascade will Cyclopamine be more powerful for blocking Cisplatin resistance. However, small molecular agents which block the Akt and/or VEGF stream have not yet been discovered. Topotec an camptothecin, a water-soluble camptothecin analog, is a novel topoisomerase I inhibitor which 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. Recently, Phase II trial showed that Topotecan is effective in both platinum sensitive and painful and platinum resistant ovarian cancers. Preclinical models have shown that Topotecan can boost platinum mediated cytotoxicity through inhibition of DNA repair. Moreover, it was reported that Topotecan induces apoptosis in human lung cancer cells, partly, by downregulating the PI3K Akt signaling pathway. These considerations led us to examine whether Topotecan inhibits the PI3K/Akt signaling pathway in ovarian cancers. More over, we evaluated thus whether Topotecan inhibits HIF 1 protein accumulation by downregulation of the PI3k/ Akt mTOR pathway in Cisplatin resistant ovarian cancers.