| Enhanced intracellular accumulation of a non-nucleoside anti-cancer agent via increased uptake of its valine ester prodrug through amino acid transporters. | |
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MedLine Citation:
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PMID: 22233275 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The phenomenon known as multiple-drug resistance, whereby anti-cancer agents are expelled from cancer cells, makes it necessary to develop methods that will reliably increase the accumulation of anti-cancer agents within cancer cells. To accomplish this goal, a new model compound, Val-SN-38, was synthesized by introducing valine to SN-38, an active ingredient of irinotecan. Val-SN-38 improved intracellular accumulation approximately 5-fold in MCF7 cells, compared with SN-38, and rather than changes in membrane permeability, the amino acid transporter ATB(0,+) played a role, whereas the dipeptide transporter PEPT1 did not. Other sodium-dependent amino acid transporters, namely ATA1, ATA2, and ASCT2, were unexpectedly involved in the uptake of Val-SN-38 as well. The efflux of Val-SN-38 by major efflux transporters was variably changed, but not significantly. In summary, the enhanced accumulation of Val-SN-38 in cancer cells was due to augmented uptake via various amino acid transporters. The results of the present study make a compelling argument in favour of a prodrug concept that can improve intracellular accumulation and take advantage of amino acid transporters without significantly inducing multiple-drug resistance. |
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Authors:
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Eun-Young Kwak; Won-Sik Shim; Ji-Eun Chang; Saeho Chong; Dae-Duk Kim; Suk-Jae Chung; Chang-Koo Shim |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-10 |
Journal Detail:
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Title: Xenobiotica; the fate of foreign compounds in biological systems Volume: - ISSN: 1366-5928 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1306665 Medline TA: Xenobiotica Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul , South Korea. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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