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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

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Summary

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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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.

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Authors and Affiliations

  1. Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    Grace-Ifeyinwa Onimoe, Aiguo Liu, Li Lin, Peter Houghton & Jiayuh Lin

  2. Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China

    Aiguo Liu

  3. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Li Lin

  4. Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan

    Chang-Ching Wei

  5. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, 43210, USA

    Eric B. Schwartz, Deepak Bhasin, Chenglong Li, James R. Fuchs & Pui-kai Li

  6. Department of Pediatrics, College of Medicine, Ohio State University and Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, USA

    Grace-Ifeyinwa Onimoe, Peter Houghton, Amanda Termuhlen, Thomas Gross & Jiayuh Lin

  7. Department of Pediatrics, Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, 43205, USA

    Jiayuh Lin

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  1. Grace-Ifeyinwa Onimoe
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  2. Aiguo Liu
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  9. Pui-kai Li
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  10. Peter Houghton
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  11. Amanda Termuhlen
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  13. Jiayuh Lin
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Correspondence to Jiayuh Lin.

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Onimoe, GI., Liu, A., Lin, L. et al. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Invest New Drugs 30, 916–926 (2012). https://doi.org/10.1007/s10637-011-9645-1

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  • DOI: https://doi.org/10.1007/s10637-011-9645-1

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