Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters

Mitsunori Okabe, Gergely Szakács, Mark A. Reimers, Toshihiro Suzuki, Matthew D. Hall, Takaaki Abe, John N. Weinstein, Michael M. Gottesman

研究成果: Article査読

122 被引用数 (Scopus)

抄録

Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.

本文言語English
ページ(範囲)3081-3091
ページ数11
ジャーナルMolecular Cancer Therapeutics
7
9
DOI
出版ステータスPublished - 2008

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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