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Organic cation transporters are determinants of oxaliplatin cytotoxicity
Shuzhong Zhang1, Katherine S Lovejoy, James E Shima
1Department of Biopharmaceutical Sciences, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94158, USA.
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 IC(50) in the six cell lines, 3.9 +/- 1.4 micromol/L (oxaliplatin) versus 11 +/- 2.0 micromol/L (cisplatin)] but was reduced by an OCT inhibitor, cimetidine, to a level similar to, or even lower than that of, cisplatin (29 +/- 11 micromol/L for oxaliplatin versus 19 +/- 4.3 micromol/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.
Insights
Organic cation transporters (OCTs) 1 and 2 enhance oxaliplatin accumulation and effectiveness against colon cancer cells, unlike cisplatin or carboplatin. This transporter specificity may explain oxaliplatin's tumor activity and guide new targeted cancer therapies.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, are mainstays in cancer treatment.
- Despite similar DNA-binding, oxaliplatin exhibits unique activity against colorectal tumors.
- The mechanisms behind oxaliplatin's tumor specificity are not fully understood, with cellular uptake being a potential factor.
Purpose of the Study:
- To investigate the role of human organic cation transporters (OCTs) 1 and 2 (SLC22A1 and SLC22A2) in the cellular uptake and cytotoxicity of platinum-based anticancer drugs.
- To determine if OCTs contribute to the tumor-specific activity of oxaliplatin.
Main Methods:
- Transfection of cells with human OCT1 and OCT2.
- Measurement of oxaliplatin, cisplatin, and carboplatin accumulation in transfected cells.
- Assessment of drug cytotoxicity using IC50 values in colon cancer cell lines.
- Evaluation of the effect of an OCT inhibitor (cimetidine) on drug cytotoxicity.
- Structure-activity relationship studies of platinum compounds.
Main Results:
- OCT1 and OCT2 significantly increased oxaliplatin accumulation and cytotoxicity in transfected cells, but not cisplatin or carboplatin.
- Oxaliplatin was more cytotoxic than cisplatin in six colon cancer cell lines.
- Inhibition of OCTs by cimetidine reduced oxaliplatin's cytotoxicity to levels similar to or lower than cisplatin.
- Specific organic functionalities on platinum drug ligands are crucial for OCT-mediated uptake.
Conclusions:
- OCT1 and OCT2 are key determinants of oxaliplatin's anticancer activity and may underlie its tumor specificity.
- Tumor expression of OCTs could serve as a biomarker for selecting platinum-based therapies.
- Targeting OCTs with novel drugs offers a new strategy for precision cancer medicine.
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