Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells.
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.
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.
Sayaka I
SI
Yamaguchi
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.
Arisa
A
Ueki
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.|Core research for evolutionary science and technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
Eiji
E
Sugihara
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.
Nobuyuki
N
Onishi
Division of Cellular Signaling, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.
Tomonori
T
Yaguchi
Division of Cellular Signaling, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.
Yutaka
Y
Kawakami
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Keisuke
K
Horiuchi
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Hideo
H
Morioka
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Morio
M
Matsumoto
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Masaya
M
Nakamura
Department of Pathophysiology, Hoshi University, Tokyo, Japan.
Akihiro
A
Muto
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Yoshiaki
Y
Toyama
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.|Core research for evolutionary science and technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
Hideyuki
H
Saya
Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.|Core research for evolutionary science and technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.|Department of Pathophysiology, Hoshi University, Tokyo, Japan.
Takatsune
T
Shimizu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077214:Becaplermin; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma; D010879:Piperazines / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta
Animal model; drug resistance; imatinib; osteosarcoma; platelet-derived growth factor (PDGF) signaling