Investigational New Drugs

, Volume 30, Issue 3, pp 916–926

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
PRECLINICAL STUDIES

DOI: 10.1007/s10637-011-9645-1

Cite this article as:
Onimoe, G., Liu, A., Lin, L. et al. Invest New Drugs (2012) 30: 916. doi:10.1007/s10637-011-9645-1

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.

Keywords

STAT3OsteosarcomaSmall molecule inhibitors

Supplementary material

10637_2011_9645_MOESM1_ESM.tif (92 kb)
ESM Table 1(TIF 91.7 kb)

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Grace-Ifeyinwa Onimoe
    • 1
    • 6
  • Aiguo Liu
    • 1
    • 2
  • Li Lin
    • 1
    • 3
  • Chang-Ching Wei
    • 4
  • Eric B. Schwartz
    • 5
  • Deepak Bhasin
    • 5
  • Chenglong Li
    • 5
  • James R. Fuchs
    • 5
  • Pui-kai Li
    • 5
  • Peter Houghton
    • 1
    • 6
  • Amanda Termuhlen
    • 6
  • Thomas Gross
    • 6
  • Jiayuh Lin
    • 1
    • 6
    • 7
  1. 1.Center for Childhood CancerThe Research Institute at Nationwide Children’s HospitalColumbusUSA
  2. 2.Department of Pediatrics, Tongji HospitalHuazhong University of Science and TechnologyWuhanChina
  3. 3.Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  4. 4.Department of PediatricsChina Medical University HospitalTaichungTaiwan
  5. 5.Division of Medicinal Chemistry and Pharmacognosy, College of PharmacyOhio State UniversityColumbusUSA
  6. 6.Department of Pediatrics, College of MedicineOhio State University and Nationwide Children’s HospitalColumbusUSA
  7. 7.Department of Pediatrics, Center for Childhood CancerThe Research Institute at Nationwide Children’s HospitalColumbusUSA