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Targeting Inflammatory Kinase as an Adjuvant Treatment for Osteosarcomas
Kyucheol Noh, MD1; Kyung-Ok Kim, PhD1; Neel R. Patel, BS1; J. Robert Staples, BS1; Hiroshi Minematsu, PhD1; Kumar Nair, BA1; Francis Young-In Lee, MD, PhD1
1 Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street, New York, NY 10032. E-mail address for F.Y.-I. Lee: fl127@columbia.edu
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Orthopaedic Science and Research Foundation. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at the Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University, New York, NY
A commentary by John H. Healey, MD, is available at www.jbjs.org/commentary and is linked to the online version of this article.

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Apr 20;93(8):723-732. doi: 10.2106/JBJS.J.00302
A commentary by John H. Healey, MD, is available here
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Abstract

Background: 

A subset of patients with aggressive osteosarcomas responds poorly to conventional cytotoxic chemotherapy. Recent evidence from studies involving the liver, skin, stomach, and colon suggests that carcinogenesis is associated with inflammation. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) has diverse roles in cancer and inflammation. The hypothesis of the present study is that targeted ERK1/2 inhibition will demonstrate anti-cancer effects in osteosarcoma both in vitro and in vivo.

Methods: 

The therapeutic effect of PD98059, a MAPK/ERK pathway inhibitor, was examined with respect to cell death, survival, and anti-apoptotic protein expression by means of flow cytometry and immunoblotting in vitro. Additionally, we transplanted green fluorescent protein and luciferase-tagged 143B osteosarcoma cells into the proximal part of the tibia of nude mice. Mice were randomly assigned to treatment with doxorubicin, PD98059, or both. Vehicle-treated mice served as controls. Treatment outcome was assessed by measuring bioluminescence and by monitoring survival.

Results: 

In vitro, ERK1/2 blockage increased the expression of pro-apoptotic proteins and increased cell death in 143B osteosarcoma cells. Doxorubicin treatment increased the expression of Bcl-2, an anti-apoptotic protein, but this upregulation was blocked by combined treatment with PD98059, suggesting a role for ERK1/2 in conferring drug resistance. In osteosarcoma-bearing mice, targeting ERK1/2 with PD98059 resulted in prolonged survival in comparison with vehicle-treated control mice (median survival time, sixty-seven days compared with seventy-four days; p = 0.0272; survival ratio = 0.9122; 95% confidence interval = 0.4354 to 1.389). Standalone doxorubicin treatment yielded similar animal morbidity (median survival time, sixty-seven days compared with seventy-six days; p = 0.0170; survival ratio = 0.8882; 95% confidence interval = 0.4181 to 1.358). Combined PD98059 and doxorubicin treatment further prolonged survival (median survival time, sixty-seven days compared with eighty-two days; p = 0.0023; survival ratio = 0.8232; 95% confidence interval = 0.3606 to 1.286).

Conclusions: 

Inhibiting ERK1/2 signaling resulted in osteosarcoma cell death by upregulating pro-apoptotic genes and inhibiting the Bcl-2-mediated resistance to doxorubicin. In osteosarcoma-bearing mice, ERK1/2 targeting alone or in combination with doxorubicin prolonged survival as compared with untreated mice.

Clinical Relevance: 

Our study highlights the anti-cancer effect of the inflammatory kinase inhibitor PD98059 on osteosarcoma cells by inducing cell death and by inhibiting a potential drug-resistance mechanism. Taken together, these results suggest that ERK signaling blockade (targeted therapy) may be considered as a new targeted adjuvant therapy for osteosarcoma.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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