Tuesday, October 8, 2013
effects of these two drugs on the cellular utilization of the PI3K/Akt
A panel of cancer cell lines and normal epithelial cell lines Celecoxib were treated with the aforementioned situation simultaneously, to test pharmacologic accumulation compared between cancer and normal cells. In line with Fig. 4A and B, AZD6244 along with API 2 successfully killed the cancer cells, whereas little toxicity was caused by the same treatment in the normal epithelial cells. Together, our results suggest that combining AZD6244 with other clinical pharmacologic agents that enhance FOXO3a activity, including API 2, may increase the effectiveness of AZD6244 therapy and even sensitize AZD6244 resistant cells to growth suppression. Given the that the mixture of AZD6244 and API 2 improved FOXO3a nuclear translocation, improved Bim ally association, rescued Bim transcriptional activation, and sensitized AZD6244 resistant cancer cells to growth suppression and cell death, we feel that FOXO3a activation is a vital element in avoiding AZD6244 opposition.
AZD6244 treatment may be also benefited by the preferential killing effect in cancer cells versus normal cells by preventing potential side effects in normal cells. A model showing Eumycetoma molecular reactions toward AZD resistant and AZD sensitive and painful cancer cells is suggested in Fig. 5B. As yet, AZD6244 has been under analysis in 21 clinical trials with about 10 different cancer types including breast cancer, colon cancer, lung cancer, melanoma, kidney cancer, hepatocellular carcinoma, pancreatic cancer, ovarian cancer, acute myelogenous leukemia, and thyroid cancer where AZD6244 has shown promising therapeutic effects particularly in cancers with BRAF strains with lower toxicity.
Other MEK inhibitors such as PD 0325901 can also be proven to have promising anti-tumor activity in mouse models but ocular and neurologic toxicity was presented in a phase I clinical study. In Fig. 5A, the mixture of API and AZD6244 2 in significant cell death in the five different cancer cell lines but not in the three different normal cell lines, suggesting that AZD6244 selectively BAY 11-7082 targets cancer cells and has relatively low toxicity to normal cells. ERK and AKT are generally activated oncogenic kinases in human cancers. Apparently, both kinases target the same tumor suppressor gene, FOXO3a. It was recognized that AKT and ERK phosphorylate FOXO3a at different phosphorylation sites.
Likewise, the phosphorylation of FOXO3a by these oncogenic kinases in FOXO3a translocation from the nucleus to the cytoplasm and subsequent degradation. Taxol, LY2940024, and API 2 were demonstrated to effectively block PI3K AKT pathway and activate FOXO3a nuclear translocation and activity. Within our present study, we confirmed that inhibition of both RAS/MEK/ ERK and PI3K/AKT pathways enhances FOXO3a activity. We showed that the service of FOXO3a and its downstream gene Bim is particularly essential for the maximal sensitivity of cancer cells responding to AZD6244 treatment.
Subscribe to:
Post Comments (Atom)
No comments:
Post a Comment