In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1522-1522
Abstract:
Members of the organic cation transporter (OCT) solute carrier family mediate the cellular uptake of a large number of structurally diverse molecules, including a variety of endogenous compounds and xenobiotics such as metformin, cimetidine, and cisplatin. OCT2 is highly expressed on the basolateral membrane of renal tubular cells, where it facilitates the renal secretion of substrate drugs. We previously found that the urinary excretion of cisplatin was drastically reduced in mice lacking the ortholog transporters Oct1 and Oct2 [Oct1/2(-/-) mice], and that, compared to wildtype mice, these animals were resistant to severe (grade 4) cisplatin-induced renal tubular necrosis. Since kidney damage was not completely abolished in Oct1/2(-/-) mice, we performed microarray analyses (Affymetrix Mouse Genome 430 v2.0) on kidney biopsies following cisplatin (10 mg/kg, i.p.) administration in order to further understand the mechanism of cisplatin-induced nephrotoxicity in these mice. Using a false-discovery rate of 5% and an average fold change of ≥2.0, we identified complex gene expression changes and a drug-response signature comprising 1063 up-regulated and 1072 down-regulated genes in wildtype mice that was strikingly different quantitatively in Oct1/2(-/-) mice. Next, we performed a KEGG pathway analysis to identify processes that are specifically altered in response to cisplatin. Ten out of 193 analyzed pathways showed significant (P & lt;0.001) alteration in wildtype mice and these changes were largely absent in Oct1/2(-/-) mice. The most significantly altered category involved genes associated with the p53 signaling network, both in wildtype mice (P=2.40×10−11) and Oct1/2(-/-) mice (P=1.92×10−8). Several well-characterized transcriptional p53 target genes such as Cdnk1a (p21), Mdm2, Bbc3 (PUMA), and Rmr2 showed strong induction in kidneys of treated wildtype mice, while their alteration was weaker or not detected in treated Oct1/2(-/-) mice. There were no mouse genotype-dependent differences in gene expression at baseline (P & gt;0.13). During the course of our screening work on identifying inhibitors of OCT2-mediated transport of cisplatin, we observed that pifithrin-α, an investigational inhibitor of p53-dependent transcriptional activation and apoptosis, is a highly potent non-competitive inhibitor of OCT2-mediated transport of tetraethylammonium, a prototypical OCT2 substrate, with a Ki of 3.0 μM. Furthermore, pifithrin-α completely blocked OCT2-mediated transport of cisplatin in vitro even at a substrate-to-inhibitor concentration ratio of 5:1. Collectively, this study suggests that (i) the ability to mount an effective p53 response in response to cisplatin is differentially influencing treatment sensitivity in wildtype mice and Oct1/2(-/-) mice, and (ii) pifithrin-α should be explored as a unique dual OCT2/p53-inhibitor for preventing cisplatin nephrotoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1522.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-1522
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
