Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells.
Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells.
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伊马替尼和阿霉素在血小板衍生的表达骨肉瘤细胞中的协同抗增殖作用。
DOI：
10.1111/cas.12686
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发表时间：
2015-07
期刊：
影响因子：
5.7
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Yamaguchi SI;Ueki A;Sugihara E;Onishi N;Yaguchi T;Kawakami Y;Horiuchi K;Morioka H;Matsumoto M;Nakamura M;Muto A;Toyama Y;Saya H;Shimizu T
骨肉瘤(OS)是最常见的骨原发实体恶性肿瘤。它的预后仍然很差，因为相当大比例的患者对化疗没有反应，因此需要新的治疗方案。我们之前建立了一个模拟人类操作系统攻击性行为的老鼠模型。用酶联免疫吸附试验对这类小鼠肿瘤裂解物进行筛选发现，血小板衍生生长因子BB是一种丰富的可溶性因子，其基因主要在肿瘤周围的非恶性细胞中表达，而同源受体(PDGFRβ)在OS细胞中高表达。无血清条件下，血小板衍生生长因子-BB可诱导MEK-ERK和磷脂酰肌醇3-激酶-蛋白激酶B信号通路的激活，促进OS细胞的存活，这些作用可被PDGF受体抑制剂伊马替尼阻断。然而，PDGF-BB和伊马替尼的这些作用在血清中大部分被掩盖。伊马替尼单独对荷瘤小鼠无抗肿瘤作用，与阿霉素联用对体内OS细胞有协同抗增殖作用。这些结果表明，只有当细胞存活依赖于PDGF信号时，或者当伊马替尼与另一种使肿瘤细胞对伊马替尼易感的治疗干预联合使用时，伊马替尼治疗OS才有效。
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.