Nverting resistant cancer sensitive to AZD6244 AZD6244 in one. Ultimately means that our study can predict FOXO3a activation is an important indicator of pharmacological efficacy may be AZD6244, in clinical use. AZD6244 is known, f rdern to cell Elvitegravir EVG cycle arrest and apoptosis via activation of ERK and inhibition tests of several clinical studies. It is therefore unerl Ugly, the detailed molecular mechanisms and downstream target genes responsible for understanding its tumor suppressor activity of t. Recently, inhibition of ERK by FOXO3a was increased Hte cell proliferation and tumorigenesis. Thus, we have attempted to determine whether AZD6244 could suppress tumor growth thanks to the activity t of FOXO3a restore.
We found that AZD6244 significantly inhibits cancer c HCT116 tumor xenograft in vivo growth and lon-treated cancer xenografts AZD6244 c Lon showed 2-hour time Ago by immunohistochemical nuclear expression of FOXO3a F Staining. To further investigate the effect of MEK inhibition on the expression of FOXO3a in vitro, we tested five different human cancer cell lines derived from three types of cancer in which AZD6244 is currently being used in Phase I / II clinical trials. We found that AZD6244 significantly inhibits ERK activation and increased Ht expression of FOXO3a in these cancer cell lines in which the cell cycle arrest and apoptosis are disturbed RKT same time. To minimize the effects of AZD6244 on cell cycle and apoptosis mediated by FOXO3a, we initially validated Highest ectopic FOXO3a GE U Ert and found that AZD6244 G1 arrest of the cell cycle, which was verst RKT improved by FOXO3a expression.
Zus Tzlich to RAS / MEK / ERK pathway, the PI3K/Akt path also known to inhibit the expression and transcriptional activity of FOXO3a t. We tested whether the combination could raise with AZD6244 PI3K/AKT pathway inhibitor LY294002 cancer cells to growth suppression and apoptosis. In fact, what AZD6244 synergistically with LY294002, the growth suppression. In addition, Taxol is the first-line drugs for treatment of breast cancer and has been shown AKT leads to the activation of FOXO3a inhibit. Thus, we also tested the t Dliche effect of the combination of AZD6244 and Taxol. We found that AZD6244 also in synergy with Taxol in the induction of apoptosis and suppression of growth.
In addition, it has been shown that FOXO3a ben for the death of AZD / taxol-induced cell Be taken, as measured in the G1 phase by dropping in FOXO3a. In addition, ectopic expression of FOXO3a in FOXO3a Murine embryonic fibroblasts leads to a 5-fold increase in apoptosis by treatment AZD6244/Taxol. Because Bim is a molecule that is activated by proapoptotic FOXO3a, we examined the r Of the FOXO3a and Bim in AZD6244/LY294002 AZD6244/Taxol and growth suppression and apoptosis mediated FOXO3a and Bim on the use of small interfering RNAs. FOXO3a and Bim down two substantially reduced effects of suppressing the growth of individual agents or a combination of AZD6244/LY294002/Taxol. Overall, our data suggest that the improvement FOXO3a expression is essential for the sensitization of cancer cells to AZD6244, and AZD6244/Taxol AZD6244/LY294002 induced growth suppression and apoptosis. Eingeschr Activity of spaces lin t and FOXO3a expression results in resistance of cancer cells in response to AZD6244 treatment, many human cancer cell lines