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Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel.

ABSTRACT: The clinical use of paclitaxel is limited by variable responses and the potential for significant toxicity. To date, studies of associations between variants in candidate genes and paclitaxel effects have yielded conflicting results. We aimed to evaluate the relationships between global gene expression and paclitaxel sensitivity.We utilized well-genotyped lymphoblastoid cell lines derived from the International HapMap Project to evaluate the relationships between cellular susceptibility to paclitaxel and global gene expression. Cells were exposed to varying concentrations of paclitaxel to evaluate paclitaxel-induced cytotoxicity and apoptosis. Among the top genes, we identified solute carrier (SLC) genes associated with paclitaxel sensitivity and narrowed down the list to those that had single nucleotide polymorphisms associated with both the expression level of the SLC gene and also with paclitaxel sensitivity. We performed an independent validation in an independent set of cell lines and also conducted functional studies using RNA interference.Of all genes associated with paclitaxel-induced cytotoxicity at P less than 0.05 (1713 genes), there was a significant enrichment in SLC genes (31 genes). A subset of SLC genes, namely SLC31A2, SLC43A1, SLC35A5, and SLC41A2, was associated with paclitaxel sensitivity and had regulating single nucleotide polymorphisms that were also associated with paclitaxel-induced cytotoxicity. Multivariate modeling demonstrated that those four SLC genes together explained 20% of the observed variability in paclitaxel susceptibility. Using RNA interference, we demonstrated increased paclitaxel susceptibility with knockdown of three SLC genes, SLC31A2, SLC35A5, and SLC41A2.Our findings are novel and lend further support to the role of transporters, specifically solute carriers, in mediating cellular susceptibility to paclitaxel.

SUBMITTER: Njiaju UO

PROVIDER: S-EPMC3376193 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel.

Njiaju Uchenna O UO Gamazon Eric R ER Gorsic Lidija K LK Delaney Shannon M SM Wheeler Heather E HE Im Hae Kyung HK Dolan M Eileen ME

Pharmacogenetics and genomics 20120701 7

<h4>Objective</h4>The clinical use of paclitaxel is limited by variable responses and the potential for significant toxicity. To date, studies of associations between variants in candidate genes and paclitaxel effects have yielded conflicting results. We aimed to evaluate the relationships between global gene expression and paclitaxel sensitivity.<h4>Methods</h4>We utilized well-genotyped lymphoblastoid cell lines derived from the International HapMap Project to evaluate the relationships betwee ...[more]

PMID: 22437668

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Project description:ObjectiveHydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia and other diseases, yet many questions remain about its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea.Materials and methodsPassive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time polymerase chain reaction in human tissues and cell lines.ResultsHydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for five different SLC transporters belonging to the organic cation/carnitine transporters and organic anion transporting polypeptides (OATP) families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time- and temperature-dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion.ConclusionsThese studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the interpatient drug variability observed in patients with sickle cell anemia.

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Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel.

Publications

Whole-genome studies identify solute carrier transporters in cellular susceptibility to paclitaxel.

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