Effects of noncovalent platinum drug-protein interactions on drug efficacy: use of fluorescent conjugates as probes for drug metabolism.
Effects of noncovalent platinum drug-protein interactions on drug efficacy: use of fluorescent conjugates as probes for drug metabolism.
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DOI：
10.1021/mp2000583
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发表时间：
2011-06-06
影响因子：
4.9
通讯作者：
Farrell NP
中科院分区：
文献类型：
--
作者：
Benedetti BT;Peterson EJ;Kabolizadeh P;Martínez A;Kipping R;Farrell NP
铂基药物的总体疗效受到共价药物-蛋白结合代谢失活的限制。本研究研究了谷胱甘肽、人血清白蛋白（HSA）和全血清与顺铂、BBR3464和TriplatinNC （BBR3464的“非共价”衍生物）结合时影响细胞毒性的因素。在用丁硫氨酸亚砜（BSO）治疗后，为了降低细胞谷胱甘肽水平，顺铂和bbr3464诱导的细胞凋亡增加，而triplatnnc诱导的细胞毒性不变。用HSA结合的顺铂（顺铂/HSA）和全血清预孵育的顺铂治疗A2780卵巢癌细胞，与单用顺铂治疗相比，细胞毒性、细胞积聚和DNA加合物形成显著降低。BBR3464也有类似的效果。相比之下，TriplatinNC、HSAbound衍生物（TriplatinNC/HSA）和用全血清预处理的TriplatinNC在所有时间点保留了相同的细胞毒性谱和相同水平的细胞积累。TriplatinNC的荧光衍生物TriplatinNC- nbd和TriplatinNC- nbd /HSA的共聚焦显微镜显示核/核仁定位模式，与HSA的溶酶体定位模式明显不同。顺铂- nbd是一种顺铂的荧光衍生物，在细胞核和整个细胞质中积累，而顺铂- nbd /HSA的定位仅限于细胞质的溶酶体区域。结果表明，triplatinncc可以避免目前临床铂类化疗药物中出现的高水平代谢失活，因此在细胞给药后保持独特的细胞毒性。
The overall efficacy of platinum based drugs is limited by metabolic deactivation through covalent drug–protein binding. In this study the factors affecting cytotoxicity in the presence of glutathione, human serum albumin (HSA) and whole serum binding with cisplatin, BBR3464, and TriplatinNC, a “noncovalent” derivative of BBR3464, were investigated. Upon treatment with buthionine sulfoximine (BSO), to reduce cellular glutathione levels, cisplatin and BBR3464-induced apoptosis was augmented whereas TriplatinNC-induced cytotoxicity was unaltered. Treatment of A2780 ovarian carcinoma cells with HSA-bound cisplatin (cisplatin/HSA) and cisplatin preincubated with whole serum showed dramatic decreases in cytotoxicity, cellular accumulation, and DNA adduct formation compared to treatment with cisplatin alone. Similar effects are seen with BBR3464. In contrast, TriplatinNC, the HSAbound derivative (TriplatinNC/HSA), and TriplatinNC pretreated with whole serum retained identical cytotoxic profiles and equal levels of cellular accumulation at all time points. Confocal microscopy of both TriplatinNC-NBD, a fluorescent derivative of TriplatinNC, and TriplatinNC-NBD/HSA showed nuclear/nucleolar localization patterns, distinctly different from the lysosomal localization pattern seen with HSA. Cisplatin-NBD, a fluorescent derivative of cisplatin, was shown to accumulate in the nucleus and throughout the cytoplasmwhile the localization of cisplatin-NBD/HSA was limited to lysosomal regions of the cytoplasm. The results suggest that TriplatinNCcan avoid high levels of metabolic deactivation currently seen with clinical platinum chemotherapeutics, and therefore retain a unique cytotoxic profile after cellular administration.
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影响因子：
16.2
作者：
CORY, AH;OWEN, TC;CORY, JG
通讯作者：
CORY, JG
影响因子：
15
作者：
Centerwall, CR;Goodisman, J;Dabrowiak, JC
通讯作者：
Dabrowiak, JC
影响因子：
2.1
作者：
Hayeshi, Rose;Masimirembwa, Collen;Ungell, Anna-Lena B.
通讯作者：
Ungell, Anna-Lena B.
影响因子：
3.6
作者：
Centerwall, Corey R.;Tacka, Kirk A.;Dabrowiak, James C.
通讯作者：
Dabrowiak, James C.
影响因子：
7.3
作者：
FARRELL, N;QU, Y;HACKER, MP
通讯作者：
HACKER, MP