There are two major apoptotic signaling pathways, the intrin

wangqian pet 11 tra 2014 - 6:00

Several protein kinases that were known to be inhibited by curcumin were not inhibited by FLLL32, These results also support the specifi city of FLLL32 to inhibit STAT3. The inhibitory efficacy of FLLL32 compared to other JAK2 and STAT3 inhibitors Finally, the growth inhibitory activities of FLL32 were compared with those previously reported inhibitors in a panel of colorectal, JAK 阻害剤 FDA approved glioblastoma, multiple myeloma and liver cancer cells lines. MTT assays were used to gener ate dose response curves and evaluate cell viability fol lowing 72 hours of treatment with different concentrations of JAK2 STAT3 inhibitors, including FLLL32, WP1066, AG490, Stattic, S3I 201, and curcu min. The IC50 values of each compound in each cell line were calculated and listed in Table 3. In our testing, FLLL32 was more potent than other compounds in the growth suppression of each cell lines tested. FLLL32 suppresses tumor growth in vivo To determine the effect of FLLL32 to suppress tumor growth, mouse xenograft experiments were then per formed to in an in vivo system. Two groups of 16 NON SCID mice were obtained for tumor xenografts LDE225 溶解度 with the MDA MB 231 breast cancer cell line. FLLL32 also could inhibit STAT3 phosphorylation and induce apoptosis in MDA MB 231 breast cancer cells, After seeding and allowing the tumors to develop for 7 days, seven mice from each group were given daily intraperitoneal doses of 50 mg kg FLLL32 whereas the other nine were given DMSO vehicle to serve as a control. The administration of FLLL32 resulted in significantly reduced tumor burdens in the MDA MB 231 xenografts in mice compared to their DMSO treated mice, These results indicated that FLLL32 not only potent オーダー LY2157299 in suppressing cancer cell growth in vitro but also potent in suppres sing tumor grow in mice in vivo. Discussion Colorectal cancer is the third most common form of can cer and the second most common cause of cancer related death in the United States. Despite advances in the treat ment of colorectal cancer, the five year survival rate has only increased to 65%. Hence, novel therapeutic approaches of more effective treatments are much needed for colorectal cancer. The constitutive activation of STAT3 is frequently detected in primary human colorectal carcinoma cells and established human colorectal cancer cell lines and elevated levels of STAT3 phos phorylation have been correlated with tumor invasion, nodal metastasis, and staging, Addition ally, constitutive STAT3 activation in colorectal cancer cells is associated with invasion, survival, and growth of colorectal cancer cells and the colorectal tumor model in mice in vivo, These reports indicate that STAT3 is one of the major oncogenic pathways activated in color ectal cancer and can serve as a promising therapeutic tar get for colorectal carcinoma. Our data in this report demonstrated that, FLLL32, a novel STAT3 inhibitor, effi ciently inhibited STAT3 phosphorylation, STAT3 DNA binding activity, which resulted the induction of apoptosis in human colorectal cancer cell lines. currently over 80,000 patients are living with multiple myeloma in the United States.