Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772;: FFC24)
Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772;: FFC24)
复制标题
DOI：
10.1016/j.bcp.2005.11.009
复制
发表时间：
2006-02-14
影响因子：
5.8
通讯作者：
Berger, W
中科院分区：
文献类型：
--
作者：
Heffeter, P;Jakupec, MA;Berger, W
本研究的目的是研究新型镧化合物[三（1，10-菲咯啉）镧（III）]三硫氰酸盐（KP 772; FFC 24）的抗癌特性。在体外，KP 772对> 60个肿瘤细胞模型的生长抑制相当，IC 50值通常在低μ M范围内。KP 772诱导肿瘤细胞凋亡的染色质凝聚，半胱天冬酶底物切割和线粒体膜去极化。DNA不太可能代表KP 772的主要分子靶标，因为在体外和活细胞中均未检测到DNA的显著相互作用或损伤。此外，我们没有发现诱导自由基物种的证据。相反，KP 772通过将细胞周期大量阻滞在G（0）/G（1）期和选择性降低cyclin B-1而有效地抑制DNA合成。虽然用KP 772处理诱导p53和p21（waf 1）的表达，但将野生型p53转染到敲除细胞中仅略微增强KP 772的细胞抑制活性。在体内，KP 772对人DLD-1结肠癌异种移植物的抗癌活性与顺铂和甲氨蝶呤在不引起显著不良反应的剂量下的抗癌活性相当。关于毒性，KP 772在Sprague-Dawley大鼠中的LD 50和无明显不良作用水平（NOAEL）分别为21.6和7.5 mg/kg，在远交白化病小鼠中分别为62和10 mg/kg。总之，KP 772通过有效诱导细胞周期停滞和/或细胞凋亡发挥抗癌活性，并对人结肠癌异种移植物具有有希望的体内抗癌活性。总之，这些数据表明KP 772作为一种新的抗癌金属药物的进一步发展。(c)2005年爱思唯尔公司All rights reserved.
Aim of this study was to investigate the anticancer properties of the new lanthanum compound [tris (1,10-phenanthroline)lanthanum (III)] trithiocyanate (KP772; FFC24). In vitro, growth inhibition by KP772 was comparable for > 60 tumour cell models with IC50 values generally in the low mu M range. KP772 induced tumour cell apoptosis indicated by chromatin condensation, caspase substrate cleavage and mitochondrial membrane depolarisation. DNA is unlikely to represent the primary molecular target of KP772, as no significant interaction or damage of DNA was detectable both in vitro and in living cells. Moreover, we found no evidence for induction of radical species. In contrast, KP772 potently inhibited DNA synthesis paralleled by a massive block of cell cycle in G(0)/G(1) phase and a selective decrease of cyclin B-1. Although treatment with KP772 induced expression of p53 and p21(waf1), transfection of wild-type p53 into knock-out cells only marginally enhanced the cytostatic activity of KP772. In vivo, the anticancer activity of KP772 against human DLD-1 colon carcinoma xenografts was comparable to that of cisplatin and methotrexate at doses not causing significant adverse effects. With regard to toxicity, the LD50 and no-observed-adverse-effect levels (NOAEL) of KP772 in Sprague-Dawley rats were 21.6 and 7.5 mg/kg, in outbred albino mice 62 and 10 mg/kg, respectively. In summary, KP772 exerts anticancer activity via potent induction of cell cycle arrest and/or apoptosis and has promising in vivo anticancer activity against a human colon cancer xenograft. Together, these data suggest further development of KP772 as a new anticancer metal-drug. (c) 2005 Elsevier Inc. All rights reserved.