Synergistic antiproliferative effect of imatinib and adriamycin in platelet‐derived growth factor receptor‐expressing osteosarcoma cells

Cancer Science

Sayaka I. Yamaguchi¹  Arisa Ueki¹  Eiji Sugihara¹  Nobuyuki Onishi¹  Tomonori Yaguchi³  Yutaka Kawakami³  Keisuke Horiuchi²  Hideo Morioka²  Morio Matsumoto²  Masaya Nakamura²  Akihiro Muto⁴  Yoshiaki Toyama²  Hideyuki Saya¹ 

[1] Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan;Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan;Department of Pathophysiology, Hoshi University, Tokyo, Japan

关键词: Animal model;    drug resistance;    imatinib;    osteosarcoma;    platelet‐derived growth factor (PDGF) signaling;   

DOI  :  10.1111/cas.12686

来源: Wiley

【 摘 要 】

Abstract

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor–BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK–ERK and phosphatidylinositol 3-kinase–protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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