Multidrug-resistant cancer cells are preferential targets of the new antineoplastic lanthanum compound KP772 (FFC24).
Multidrug-resistant cancer cells are preferential targets of the new antineoplastic lanthanum compound KP772 (FFC24).
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DOI：
10.1016/j.bcp.2007.03.002
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发表时间：
2007-06-15
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, M. A.;Koerner, W.;Chiba, P.;Pirker, C.;Dornetshuber, R.;Elbling, L.;Sutterluety, H.;Micksche, M.;Keppler, B. K.;Berger, W.
最近，我们介绍了[三（1，10-菲咯啉）镧（III）]三硫氰酸盐（KP 772，FFC 24）作为一种新的镧化合物，在体内和体外具有良好的抗癌性能。本研究的目的是研究ABC转运蛋白介导的多药耐药（MDR）对KP 772抗癌活性的影响。在这里，我们证明了所有MDR细胞模型研究，过度表达ABCB 1（P-糖蛋白），ABCC 1（多药耐药蛋白1），或ABCG 2（乳腺癌耐药蛋白），无论是由于药物选择或基因转染，显着超敏对KP 772。使用ABCB 1过表达的KBC-1细胞作为MDR模型，KP 772超敏反应被证明是基于在未改变的细胞药物积累下更强的凋亡诱导和/或细胞周期停滞。KP 772既不刺激ABCB 1 ATP酶活性，也不改变罗丹明123的积累，反对与ABCB 1的直接相互作用。因此，几种耐药调节剂不敏化，而是保护MDR细胞免受KP 772诱导的细胞毒性。此外，以亚毒性浓度长期KP 772处理KBC-1细胞，由于MDR 1基因表达被阻断，在20次传代内导致耐药性完全丧失。当将亲本KB-3-1细胞暴露于亚毒性、逐步增加的KP 772浓度时，我们观察到，与其他几种金属药物相反，没有获得KP 772抗性。总之，我们的数据表明，KP 772在MDR细胞中是高活性的，并且可能通过阻断ABCB 1表达而具有化学增敏特性。连同肿瘤细胞获得KP 772抗性的能力，我们的数据表明KP 772应该对众所周知的耐药肿瘤类型特别有效，并作为标准化疗失败后的二线治疗。
Recently, we have introduced [tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772, FFC24) as a new lanthanum compound which has promising anticancer properties in vivo and in vitro. Aim of this study was to investigate the impact of ABC transporter-mediated multidrug resistance (MDR) on the anticancer activity of KP772. Here, we demonstrate that all MDR cell models investigated, overexpressing ABCB1 (P-glycoprotein), ABCC1 (multidrug resistance protein 1), or ABCG2 (breast cancer resistance protein) either due to drug selection or gene transfection, were significantly hypersensitive against KP772. Using ABCB1-overexpressing KBC-1 cells as MDR model, KP772 hypersensitivity was demonstrated to be based on stronger apoptosis induction and/or cell cycle arrest at unaltered cellular drug accumulation. KP772 did neither stimulate ABCB1 ATPase activity nor alter rhodamine 123 accumulation arguing against a direct interaction with ABCB1. Accordingly, several drug resistance modulators did not sensitize but rather protect MDR cells against KP772-induced cytotoxicity. Moreover, long-term KP772 treatment of KBC-1 cells at subtoxic concentrations led within 20 passages to a complete loss of drug resistance based on blocked MDR1 gene expression. When exposing parental KB-3-1 cells to subtoxic, stepwise increasing KP772 concentrations, we observed, in contrast to several other metallo-drugs, no acquisition of KP772 resistance. Summarizing, our data demonstrate that KP772 is hyperactive in MDR cells and might have chemosensitizing properties by blocking ABCB1 expression. Together with the disability of tumor cells to acquire KP772 resistance, our data suggest that KP772 should be especially active against notoriously drug-resistant tumor types and as second line treatment after standard chemotherapy failure.
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DOI：
10.1073/pnas.0505337102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Huh, KW;DeMasi, J;Münger, K
通讯作者：
Münger, K
DOI：
10.1124/jpet.104.073395
发表时间：
2005-01-01
影响因子：
3.5
作者：
Heffeter, P;Pongratz, M;Berger, W
通讯作者：
Berger, W
影响因子：
5.8
作者：
Fattman, CL;Allan, WP;Yalowich, JC
通讯作者：
Yalowich, JC
影响因子：
5.8
作者：
Heffeter, P;Jakupec, MA;Berger, W
通讯作者：
Berger, W
DOI：
10.1073/pnas.95.26.15665
发表时间：
1998-12-22
影响因子：
11.1
作者：
Doyle, LA;Yang, WD;Ross, DD
通讯作者：
Ross, DD