Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (FFC14A)
Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (FFC14A)
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DOI：
10.1124/jpet.104.073395
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Berger, W
中科院分区：
文献类型：
--
作者：
Heffeter, P;Pongratz, M;Berger, W
KP 1019 [反式-[四氯二（1H-吲唑）双烯酸盐（III）]（FFC 14 A）是一种具有良好抗癌活性的金属配合物。由于耐药性是化疗的主要障碍，本研究调查了几种耐药机制对KP 1019抗癌活性的影响。在这里，我们证明了KP 1019的细胞毒性作用既不实质上阻碍了过度表达的耐药蛋白多药耐药相关蛋白1，乳腺癌耐药蛋白，肺耐药蛋白，也不是转铁蛋白受体，只有轻微的细胞p53状态。相比之下，P-糖蛋白过表达弱，但显着（高达2倍）降低KP 1019的活性。P-糖蛋白相关的耐药性是基于细胞内KP 1019积累的减少，并且可以通过已知的P-糖蛋白调节剂逆转。KP 1019剂量依赖性地抑制P-糖蛋白的ATP酶活性，Ki值约为31 μ M。此外，它在无血清条件下有效地阻断P-糖蛋白介导的罗丹明123流出（EC 50，类似于8 μ M），然而，在增加的血清浓度下活性降低（EC 50在10%血清，类似于35 μ M）。此外，P-糖蛋白介导的柔红霉素抗性只能在含血清培养基中由KP 1019轻微恢复，这也表明血清蛋白对KP 1019和P-糖蛋白之间的相互作用的影响。通过选择针对KP 1019的KB-3-1细胞超过1年来研究获得性KP 1019抗性。仅可诱导类似于2倍的KP 1019抗性，这出乎意料地不是由于P-糖蛋白或其他外排泵的过表达。因此，KP 1019抗性细胞没有显示出减少的药物积累。它们独特的交叉耐药模式证实了ABC转运蛋白非依赖性耐药表型。总之，在治疗期间获得对KP 1019不敏感的可能性预计较低，并且耐药不应基于药物外排转运蛋白的过表达。
KP1019 [indazolium trans-[tetrachlorobis(1H-indazole) ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly ( up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K-i of similar to31 muM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC50, similar to 8 muM), however, with reduced activity at increased serum concentrations (EC50 at 10% serum, similar to 35 muM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an similar to2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.