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

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 10/2008; 7(9):3081-91. DOI: 10.1158/1535-7163.MCT-08-0539
Source: PubMed

ABSTRACT

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.

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Available from: Matthew D Hall, Feb 28, 2014
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    • "Huang and colleagues correlated SLC gene expression profiles in the NCI-60 cancer cell line panel with the potencies of 119 standard anticancer drugs and identified new transporter substrates (Huang et al., 2004 ). More recently , a similar approach was carried out by Okabe et al. (2008) to investigate the SLC22 and SLCO gene families using quantitative reverse transcription-polymerase chain reaction array rather than oligonucleotide array. That work revealed the role of SLC22A4 in cellular sensitivity to doxorubicin and mitoxantrone. "
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    • "Among the SLCO family members, SLCO5A1 is the only gene which is located on chromosome 8 (8q13.3). High mRNA levels were detected in the brain, heart, skeletal muscle, and ovary [16]. SLCO5A1 was observed in human bone tumors, in prostate cancer [17] and in normal and cancerous breast tissue [18]. "
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    • "However, recent results indicate that at least the two OATP isoforms primarily expressed in the liver, namely, OATP1B1 and OATP1B3, are electrogenic transporters, although their activity may be strongly affected under circumstances of abnormal variations of local pH [13]. This is pharmacologically important because tumour environment is often acidic and both transporters can be the gate for the entrance in liver tumours of many cytostatic drugs [14], such as irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) [15], flavopiridol [16], methotrexate [17], paclitaxel [18], and several bile acid-cisplatin conjugates (BAMET) [19]. OATP2B1 is expressed in territories other than liver, where this transporter is involved in the uptake of different drugs. "
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