Nephrotoxicity of platinum complexes is related to basolateral organic cation transport

Ludwig, Thomas; Riethmüller, Christoph; Gekle, Michael; Schwerdt, Gerald; Oberleithner, Hans

doi:10.1111/j.1523-1755.2004.00720.x

Cited by 160 publications

(115 citation statements)

References 42 publications

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“…AOAA clinicopathologically ameliorated cisplatin nephrotoxicity (Table 2), as was the case in male C57BL/6 mice (Townsend and Hanigan 2002), although the rats receiving AOAA exhibited severe clinical signs on day 1. The renal Pt residue on day 5 did not differ between the cisplatin-alone and cisplatin + AOAA groups, demonstrating that elimination processes of cisplatin via the organic cation transporters, especially OCT2 (Ludwig et al 2004) may not be disturbed by pretreatment with AOAA.…”

Section: Discussionmentioning

confidence: 81%

Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity

Katayama

Nagata

Iida

et al. 2011

Food and Chemical Toxicology

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Section: Discussionmentioning

confidence: 81%

Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity

Katayama

Nagata

Iida

et al. 2011

Food and Chemical Toxicology

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“…The presence of these transporters in certain organs, most notably kidney and liver, may require the use of cotreatments to mitigate toxic side effects. Nephrotoxicity, the doselimiting side effect for cisplatin therapy, is less problematic in oxaliplatin treatment (34). Liver toxicity is a non-dose-limiting side effect of cisplatin and oxaliplatin (35).…”

Section: Removal Of Lesions By Excision Repairmentioning

confidence: 99%

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Lovejoy

Todd

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

228

221

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We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH 3)2(py)Cl]؉ or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH ‫؍‬ trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH 3)2(py)} 2؉ bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5 side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)} 2؉ . cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.cancer therapy ͉ nucleotide excision repair ͉ organic cation transporter ͉ RNA polymerase II inhibition ͉ x-ray crystal structure

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“…Different sensitivity might be explained by greater cisplatin uptake in LLC-PK1 cells. Several studies report cisplatin is transported into renal proximal tubular cells via renal organic cation transporter 2 (OCT2) (Ciarimboli et al, 2005;Ludwig et al, 2004) which expresses in LLC-PK1 (Okuda et al, 1999) but not in HK-2 cells (Jenkinson et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways

et al. 2016

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-Cisplatin is widely used as a standard chemotherapy for solid tumors. The major adverse effect of cisplatin is nephrotoxicity in proximal tubular cells, via oxidative stress, DNA damage, cell apoptosis, and inflammation. The aim of this study was to investigate the pharmacological effect and mechanism of fibrate drugs on cisplatin-induced renal proximal tubular cell death. Cisplatin decreased cell viability of LLC-PK1 and HK-2 cells in a dose-dependent manner. Cisplatin-induced apoptosis was attenuated by co-treatment with fenofibrate while less so with clofibrate and bezafibrate. Fenofibrate's protective effect was not complimented by co-treatment with GW6471, a PPARα antagonist, indicating the protective effect occurred via a PPARα-independent mechanism. Treating cells with cisplatin induced reactive oxygen species (ROS), c-JUN N-terminal kinase (JNK), and p38 kinase (p38), but not extracellular signal-regulated kinase (ERK). Fenofibrate reversed cisplatin-induced JNK and p38 activation, but had no effect on ROS production. The findings suggest fenofibrate's protective effect on cisplatin-induced cytotoxicity is mediated by inhibition of JNK and p38. Moreover, fenofibrate did not alter cisplatin's antitumor effect on cancer cell lines including T84, SW-480, HepG2, and SK-LU-1 cells. Therefore, fenofibrate may be a candidate agent for further development as an adjuvant to cisplatin treatment.

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Nephrotoxicity of platinum complexes is related to basolateral organic cation transport

Abstract: Toxic effects of platinum complexes on renal epithelia depend on the platinum complex used and the site of application. We conclude that cell polarity and basolateral transport mechanisms are essential in nephrotoxicity of platinum drugs.

Cited by 160 publications

References 42 publications

Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity

Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways

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