Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice

Grace Ifeyinwa Onimoe; Aiguo Liu; Li Lin; Chang Ching Wei; Eric B. Schwartz; Deepak Bhasin; Chenglong Li; James R. Fuchs; Pui Kai Li; Peter Houghton; Amanda Termuhlen; Thomas Gross; Jiayuh Lin

doi:10.1007/s10637-011-9645-1

Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice

Grace Ifeyinwa Onimoe, Aiguo Liu, Li Lin, Chang Ching Wei, Eric B. Schwartz, Deepak Bhasin, Chenglong Li, James R. Fuchs, Pui Kai Li, Peter Houghton, Amanda Termuhlen, Thomas Gross, Jiayuh Lin

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Abstract

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

Original language	English (US)
Pages (from-to)	916-926
Number of pages	11
Journal	Investigational New Drugs
Volume	30
Issue number	3
DOIs	https://doi.org/10.1007/s10637-011-9645-1
State	Published - Jun 2012

Bibliographical note

Funding Information:
Acknowledgements This work was supported by a pilot grant from the Experimental Therapeutics Program at the Ohio State University Comprehensive Cancer Center and a grant from the Hematology and Oncology Department at the Nationwide Children’s Hospital.

Keywords

Osteosarcoma
STAT3
Small molecule inhibitors

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Onimoe, G. I., Liu, A., Lin, L., Wei, C. C., Schwartz, E. B., Bhasin, D., Li, C., Fuchs, J. R., Li, P. K., Houghton, P., Termuhlen, A., Gross, T., & Lin, J. (2012). Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Investigational New Drugs, 30(3), 916-926. https://doi.org/10.1007/s10637-011-9645-1

Onimoe, GI, Liu, A, Lin, L, Wei, CC, Schwartz, EB, Bhasin, D, Li, C, Fuchs, JR, Li, PK, Houghton, P, Termuhlen, A, Gross, T & Lin, J 2012, 'Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice', Investigational New Drugs, vol. 30, no. 3, pp. 916-926. https://doi.org/10.1007/s10637-011-9645-1

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abstract = "Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.",

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N2 - Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

AB - Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

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Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice

Abstract

Bibliographical note

Keywords

UN SDGs

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