PKC412--a protein kinase inhibitor with a broad therapeutic potential.
PKC412--a protein kinase inhibitor with a broad therapeutic potential.
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发表时间：
2000-02
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通讯作者：
Doriano Fabbro;S. Ruetz;Stephan Bodis;M. Pruschy;K. Csermak;Anthony Man;P. Campochiaro;J. Wood;Terence O'reilly;Thomas F. Meyer
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作者：
Doriano Fabbro;S. Ruetz;Stephan Bodis;M. Pruschy;K. Csermak;Anthony Man;P. Campochiaro;J. Wood;Terence O'reilly;Thomas F. Meyer
星形孢菌素衍生物PKC 412最初被鉴定为蛋白激酶C（PKC）的抑制剂，随后显示出抑制其他激酶，包括激酶插入结构域受体（KDR）（血管内皮生长因子受体，VEGF-R2）、血小板衍生生长因子受体和干细胞因子受体c-kit。PKC 412在体外对多种肿瘤和正常细胞系显示出广泛的抗增殖活性，并且能够逆转Pgp介导的肿瘤细胞的多药耐药。细胞暴露于PKC 412导致细胞周期的G2/M期的剂量依赖性增加，伴随着多倍体增加、凋亡和对电离辐射的敏感性增强。PKC 412作为单一药剂显示出有效的抗肿瘤活性，并且能够增强一些临床上使用的细胞毒素（紫杉醇和多柔比星）在体内的抗肿瘤活性。PKC 412与局部区域电离辐射的联合治疗显示出对电离辐射和化疗药物均耐药的肿瘤（功能失调的p53）的显著抗肿瘤活性。PKC 412是VEGF介导的细胞信号传导的抑制剂，通过在体外抑制KDR和PKC的发现与生长因子植入模型中VEGF依赖性血管生成的体内抑制一致。口服给药的PKC 412也强烈抑制视网膜新生血管以及激光诱导的脉络膜新生血管在小鼠模型。总之，除了通过其对PKC和/或其他蛋白激酶的作用直接抑制肿瘤细胞增殖之外，PKC 412还可以通过抑制肿瘤血管生成来抑制肿瘤生长。PKC 412目前正在进行治疗晚期癌症和治疗缺血性视网膜病变的I期临床试验。
The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.