Glioblastoma continues to have KPT-330 mw very poor prog nosis despite advances in chemotherapy and radiation therapy. Many clinical cases of glioblastoma and glioblastoma cell lines e press constitutively activated STAT3. Overe pression of IL 6, an upstream regulator of STAT3 is also detected in glioblastoma and is a marker of malignancy. The persistent activation of STAT3 is in part, also attributable to an autocrine action of IL 6 in the glioblastoma cells. However, STAT3 was reported to play a pro oncogenic or tumor suppressive role depending on the the genetic background of the tumor. Our results showed that FLLL32 was a potent inhibitor in inhibiting STAT3 phosphorylation and STAT3 DNA binding activity in human glioblastoma cell lines. Human glioblastoma cells were induced to apoptosis by the inhibition of STAT3 with FLLL32.
Furthermore, the inhibitory efficacy of FLLL32 in liver cancer cells was e amined. Liver cancer or hepatocellu lar carcinoma is one of the most serious of cancers. According to the American Cancer Society, the five year relative survival rates are currently at 11% for all stages, 7. 7% for regional metastasis, and 2. 9% for distant metas tasis. Hence, there is an urgent need to develop more effective treatments for liver cancer. Patients with any stage of liver cancer may appropriately be considered candidates for clinical trials using new inhibitors because of the poor response to chemotherapy as con ventionally used. The constitutive activation of STAT3 is frequently detected in clinical incidences of liver can cer and in more than 50% of human liver cancer cell lines but not in normal or non transformed human cells.
The constitutive activation of STAT3 in liver cancer is frequently due to the aberrant methylation and silencing of Suppressor of Cytokine signaling 1 and 3. Constitutive STAT3 signal ing contributes to liver cancer progression by promoting angiogenesis, survival, metastasis, and growth of liver cancer cells. Again, our data demonstrated that FLLL32 could efficiently inhibit STAT3 phosphorylation and induced apoptosis in four independent human liver cancer cell lines. These results indicate that FLLL32 also has potential as a therapeutic agent for liver cancer cells e pressing persistently activated STAT3. In addition, FLLL32 also potent to inhibit STAT3 phosphorylation and induce apoptosis in MDA MB 231 breast cancer cells.
The potency of FLLL32 was further confirmed in MDA MB 231 breast cancer enografts in mouse model in vivo. Therefore, FLLL32 is not only potent in cancer cells in vitro but also in tumor cells in animal model in vivo and may have future potential to target tumor cells that e press persistently activated STAT3 Cilengitide in cancer patients. Curcumin has been demonstrated as a dietary agent that can inhibit STAT3.