Organic cation transporters are determinants of oxaliplatin cytotoxicity

Shuzhong Zhang, Katherine S. Lovejoy, James E. Shima, Leah L. Lagpacan, Yan Shu, Anna Lapuk, Ying Chen, Takafumi Komori, Joe Gray, Xin Chen, Stephen J. Lippard, Kathleen M. Giacomini

Research output: Contribution to journalArticle

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Abstract

Although the platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin have similar DNA-binding properties, only oxaliplatin is active against colorectal tumors. The mechanisms for this tumor specificity of platinum-based compounds are poorly understood but could be related to differences in uptake. This study shows that the human organic cation transporters (OCT) 1 and 2 (SLC22A1 and SLC22A2) markedly increase oxaliplatin, but not cisplatin or carboplatin, accumulation and cytotoxicity in transfected cells, indicating that oxaliplatin is an excellent substrate of these transporters. The cytotoxicity of oxaliplatin was greater than that of cisplatin in six colon cancer cell lines [mean ± SE of IC50 in the six cell lines, 3.9 ± 1.4 μmol/L (oxaliplatin) versus 11 ± 2.0 μmol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 ± 11 μmol/L for oxaliplatin versus 19 ± 4.3 μmol/L for cisplatin). Structure-activity studies indicated that organic functionalities on nonleaving groups coordinated to platinum are critical for selective uptake by OCTs. These results indicate that OCT1 and OCT2 are major determinants of the anticancer activity of oxaliplatin and may contribute to its antitumor specificity. They also strongly suggest that expression of OCTs in tumors should be investigated as markers for selecting specific platinum-based therapies in individual patients. The development of new anticancer drugs, specifically targeted to OCTs, represents a novel strategy for targeted drug therapy. The results of the present structure-activity studies indicate specific tactics for realizing this goal.

Original languageEnglish (US)
Pages (from-to)8847-8857
Number of pages11
JournalCancer Research
Volume66
Issue number17
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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oxaliplatin
Cations
Cisplatin
Platinum
Carboplatin
Organic Cation Transporter 1
Platinum Compounds
Cell Line
Cimetidine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhang, S., Lovejoy, K. S., Shima, J. E., Lagpacan, L. L., Shu, Y., Lapuk, A., ... Giacomini, K. M. (2006). Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Research, 66(17), 8847-8857. https://doi.org/10.1158/0008-5472.CAN-06-0769

Organic cation transporters are determinants of oxaliplatin cytotoxicity. / Zhang, Shuzhong; Lovejoy, Katherine S.; Shima, James E.; Lagpacan, Leah L.; Shu, Yan; Lapuk, Anna; Chen, Ying; Komori, Takafumi; Gray, Joe; Chen, Xin; Lippard, Stephen J.; Giacomini, Kathleen M.

In: Cancer Research, Vol. 66, No. 17, 01.09.2006, p. 8847-8857.

Research output: Contribution to journalArticle

Zhang, S, Lovejoy, KS, Shima, JE, Lagpacan, LL, Shu, Y, Lapuk, A, Chen, Y, Komori, T, Gray, J, Chen, X, Lippard, SJ & Giacomini, KM 2006, 'Organic cation transporters are determinants of oxaliplatin cytotoxicity', Cancer Research, vol. 66, no. 17, pp. 8847-8857. https://doi.org/10.1158/0008-5472.CAN-06-0769
Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Research. 2006 Sep 1;66(17):8847-8857. https://doi.org/10.1158/0008-5472.CAN-06-0769
Zhang, Shuzhong ; Lovejoy, Katherine S. ; Shima, James E. ; Lagpacan, Leah L. ; Shu, Yan ; Lapuk, Anna ; Chen, Ying ; Komori, Takafumi ; Gray, Joe ; Chen, Xin ; Lippard, Stephen J. ; Giacomini, Kathleen M. / Organic cation transporters are determinants of oxaliplatin cytotoxicity. In: Cancer Research. 2006 ; Vol. 66, No. 17. pp. 8847-8857.
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AU - Shu, Yan

AU - Lapuk, Anna

AU - Chen, Ying

AU - Komori, Takafumi

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AU - Chen, Xin

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