Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines.
Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines.
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DOI：
10.1158/1535-7163.mct-09-0115
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Hornicek FJ
中科院分区：
文献类型：
--
作者：
Duan Z;Choy E;Harmon D;Yang C;Ryu K;Schwab J;Mankin H;Hornicek FJ
胰岛素样生长因子-1受体（IGF-1 R）是肿瘤细胞存活的重要介质，在肉瘤中具有预后意义。为了探索潜在的治疗策略，中断信号通过这一途径，我们评估的能力，环木脂素picropodophyllin（PPP），环木脂素家族的成员，选择性抑制受体酪氨酸激酶（RTK）活性的IGF-1 R在几个肉瘤细胞系模型系统。在研究的各种肉瘤亚型中，发现骨肉瘤细胞系对IGF-1 R抑制特别敏感，包括几种对各种常规抗癌药物具有耐药性的多药耐药骨肉瘤细胞系。与骨肉瘤细胞系相比，PPP在人成骨细胞系中显示出相对较小的毒性。这些研究表明，PPP显着抑制IGF-1 R的表达和激活在化疗敏感和耐药的骨肉瘤细胞系。IGF 1-R通路的这种抑制与骨肉瘤细胞系增殖的抑制和细胞凋亡诱导相关，如通过监测PARP及其裂解产物和通过定量测量细胞凋亡相关的CK 18 Asp 396所测量的。重要的是，PPP增加了阿霉素耐药骨肉瘤细胞系U-2 OSMR和KHOSMR中阿霉素的细胞毒性作用。此外，siRNA下调IGF-1 R在耐药细胞系中的表达也引起对阿霉素的再致敏。我们的数据表明，PPP抑制IGF-1 R为骨肉瘤提供了一种新的选择性治疗策略，同时PPP可有效逆转骨肉瘤细胞系的耐药表型。
Insulin-like growth factor-1 receptor (IGF-1R) is an important mediator of tumor-cell survival and demonstrates prognostic significance in sarcoma. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of cyclolignan picropodophyllin (PPP), a member of the cyclolignan family, to selectively inhibit the receptor tyrosine kinase (RTK) activity of IGF-1R in several sarcoma cell line model systems. Of the diverse sarcoma subtypes studied, osteosarcoma cell lines were found to be particularly sensitive to IGF-1R inhibition, including several multidrug resistant osteosarcoma cell lines with documented resistance to various conventional anticancer drugs. PPP shows relatively little toxicity in human osteoblast cell lines when compared to osteosarcoma cell lines. These studies demonstrate that PPP significantly inhibits IGF-1R expression and activation in both chemotherapy sensitive and resistant osteosarcoma cell lines. This inhibition of the IGF1-R pathway correlates with suppression of proliferation of osteosarcoma cell lines and with apoptosis induction as measured by monitoring PARP and its cleavage product and by quantitative measurement of apoptosis-associated CK18Asp396. Importantly, PPP increases the cytotoxic effects of doxorubicin in doxorubicin-resistant osteosarcoma cell lines U-2OSMR and KHOSMR. Furthermore, siRNA down-regulation of IGF-1R expression in drug resistant cell lines also caused re-sensitization to doxorubicin. Our data suggests that inhibition of IGF-1R with PPP offers a novel and selective therapeutic strategy for ostosarcoma, and at the same time, PPP is effective at reversing the drug-resistance phenotype in osteosarcoma cell lines.