LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model
Fuh, B; Sobo, M; Cen, L; Josiah, D; Hutzen, B; Cisek, K; Bhasin, D; Regan, N; Lin, L; Chan, C; Caldas, H; DeAngelis, S; Li, C; Li, P-K; Lin, J
Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study, we investigated the inhibitory effects of a small molecule compound known as LLL-3, which is a structural analogue of the earlier reported STAT3 inhibitor, STA-21, on the cell viability of human glioblastoma cells, U87, U373, and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87, U373, and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines as evidenced by increased poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavages. Furthermore, the U87 glioblastoma tumour-bearing mice treated with LLL-3 exhibited prolonged survival relative to vehicle-treated mice (28.5 vs 16 days) and had smaller intracranial tumours and no evidence of contralateral invasion. These results suggest that LLL-3 may be a potential therapeutic agent in the treatment of glioblastoma with constitutive STAT3 activation. Originally published in British Journal of Cancer 2009 Vol. 110, No. 1
Fuh, B, & Sobo, M, & Cen, L, & Josiah, D, & Hutzen, B, & Cisek, K, & Bhasin, D, & Regan, N, & Lin, L, & Chan, C, & Caldas, H, & DeAngelis, S, & Li, C, & Li, P-K, & Lin, J. (January 2009). LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. British Journal of Cancer, 100(1), 106- 112. Retrieved from http://hdl.handle.net/10342/3001
Fuh, B, and Sobo, M, and Cen, L, and Josiah, D, and Hutzen, B, and Cisek, K, and Bhasin, D, and Regan, N, and Lin, L, and Chan, C, and Caldas, H, and DeAngelis, S, and Li, C, and Li, P-K, and Lin, J. "LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model". British Journal of Cancer. 100:1. (106-112), January 2009. October 17, 2018. http://hdl.handle.net/10342/3001.
Fuh, B and Sobo, M and Cen, L and Josiah, D and Hutzen, B and Cisek, K and Bhasin, D and Regan, N and Lin, L and Chan, C and Caldas, H and DeAngelis, S and Li, C and Li, P-K and Lin, J, "LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model," British Journal of Cancer 100, no. 1 (January 2009), http://hdl.handle.net/10342/3001 (accessed October 17, 2018).
Fuh, B, Sobo, M, Cen, L, Josiah, D, Hutzen, B, Cisek, K, Bhasin, D, Regan, N, Lin, L, Chan, C, Caldas, H, DeAngelis, S, Li, C, Li, P-K, Lin, J. LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. British Journal of Cancer. January 2009; 100(1): 106-112. http://hdl.handle.net/10342/3001. Accessed October 17, 2018.
East Carolina University