We investigated whether inhibition of nuclear factor-B (NF B) increases the efficacy of paclitaxel in in vitro

Whether or not inhibition of NFB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of IB␣ and activity of NFB between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of IB␣ and activity of NFB in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of IB␣ and activity of NFB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of IB␣ and activation of NFB and less marked inhibition of the phosphorylation of IB␣ and activation of NFB by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NFB activity either by treatment with the IB␣ phosphorylation inhibitor (BAY 11-7085) or a specific NFB nuclear translocation inhibitor (SN-50) or by transfection of p50⌬NLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of IB␣ phosphorylation and NFB activity and the cisplatininduced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NFB inhibitor should increase the therapeutic efficacy of cisplatin.The sensitivity of cells to chemotherapeutic drug-induced apoptosis appears to depend on the balance between proapoptotic and antiapoptotic signals. Therefore, it is possible that antiapoptotic signals such as the PI3K 1 -Akt survival cascade are involved in sensitivity to chemotherapeutic drugs. We reported that Akt inactivation sensitizes human ovarian cancer cells to cisplatin (1) and paclitaxel (2), suggesting that Akt inactivation could be a hallmark for examining the sensitivity of cells to some chemotherapeutic drugs. Possible mechanisms by which Akt promotes cell survival include phosphorylation and inactivation of the proapoptotic proteins BAD and caspase-9 (3, 4). Akt also phosphorylates and inactivates the Forkhead transcription factors, resulting in reduced expression of the cell cycle inhibitor p27 Kip1 and the Fas ligand (5-7). Via the phosphorylation of IB kinase, Akt also activates NFB, a transcription factor that has been implicated in cell survival (8,9).NFB is activated in certain cancers and in response to chemotherapy and radiation. NFB normally resides in the cytoplasm as an inactivated form in a complex with IB␣. Phosphorylation of IB␣ by upstream kinases promotes its degradation, allowing NFB to translocate to the nucleus and induce target genes (6, 7). The transcriptional activation of genes associa...

Vascular endothelial growth factor

The phosphatidylinositol 3-kinase (PI3K)/Akt cascade has an important role in the resistance of ovarian cancer cells to cisplatin in vitro; however, there have been no reports about whether blocking the PI3K/Akt cascade enhances the sensitivity to cisplatin in vivo. We investigated whether inhibition of PI3K increased the efficacy of cisplatin in an in vivo ovarian cancer model. Blocking the PI3K/Akt cascade with a PI3K inhibitor (wortmannin) increased the efficacy of cisplatin-induced inhibition of intraabdominal dissemination and production of ascites in athymic nude mice inoculated ip with the Caov-3 human ovarian cancer cell line. In addition, wortmannin increased the efficacy of cisplatin-induced apoptosis in tumors cells. There were no detectable side effects in mice treated with wortmannin. Moreover, the antitumor effect of cisplatin detected in mice inoculated with Caov-3 cells stably transfected with empty vector was significantly attenuated, compared with mice inoculated with Caov-3 cells stably transfected with a dominant-negative Akt, K179M-Akt. We confirmed that wortmannin blocked Akt phosphorylation and the downstream targets of the PI3K/Akt cascade, such as BAD (Bcl-2-associated death protein) and nuclear factor-kappaB in vivo by immunohistochemical staining and Western blotting. In accordance with the previously reported in vitro results, these in vivo results support the idea that combination therapy with cisplatin and a PI3K inhibitor would increase the therapeutic efficacy of cisplatin.

Aim: To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2015 and the Annual Treatment Report for 2010 on the outcomes of patients who started treatment in 2010. Methods: The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment was initiated in 2015 were analyzed retrospectively. Survival of the patients who started treatment in 2010 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxson tests. Results: Treatment was initiated in 2015 for 7527 patients with cervical cancer, 10 119 with endometrial cancer, 6424 with ovarian cancer and 2181 with ovarian borderline tumors. This clinicopathological information was summarized as the Patient Annual Report. Prognoses were analyzed across 4309 patients with cervical cancer, 5054 with endometrial cancer and 3423 with ovarian cancer, whose treatment was initiated in 2010. The 5-year survival rates of the patients with cervical cancer were 92.1%, 74.2%, 52.0%, and 29.8% for stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 94.3%, 88.8%, 74.0% and 26.6% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 88.5%, 80.1%, 46.3% and 36.2% for stages I, II, III and IV, respectively. Conclusion: The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.