Review
Solute Carrier Transporters as Targets for Drug Delivery and Pharmacological Intervention for Chemotherapy

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Abstract

Many solute carrier transporters that interact with anticancer agents and contribute to their pharmacokinetics have been shown to be differentially upregulated in cancer cells as a result of adaptive response to altered nutritional requirements. This review focuses on pathophysiological function of membrane transporters responsible for the influx of physiological substances including oligopeptides, amino acids, and organic cations and anions, and summarizes the recent knowledge regarding mechanisms in their gene expressions. Broad substrate specificity of enhanced oligopeptide H+/peptide cotransporter 1 activity in cancer cells is useful for tumor tissue-specific delivery of chemotherapeutic agents and positron emission tomography diagnostic probes. Amino acid transporters such as LAT1 and ASCT2 are upregulated in human cancer cells and are thought to stimulate tumor growth by regulating mammalian target of rapamycin through nutrient pathway. Especially, LAT1 could be a molecular target to deprive cancer cells of amino acids in combination with aminopeptidase inhibitors. As organic anion transporting polypeptides carry estrone-3-sulfate that is intracellularly hydrolyzed to estrone, their overexpression may provide a pharmacological merit to treat hormone-responsive breast tumors. Therefore, it is important to understand the pathophysiological significance and gene expression in cancer to develop new rationales for drug delivery and pharmacological interventions for chemotherapy. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3731–3750, 2011

Section snippets

INTRODUCTION

Plasma membrane transporter proteins are encoded by numerous gene families and play key roles in cell survival by regulating the influx and efflux of myriad substances across the plasma membranes. On the basis of function, transporter proteins are divided into two superfamilies, that is, the solute carrier (SLC) and the ATP-binding cassette (ABC) transporters. Most of the SLC family members function as influx transporters for nutrients and substances essential for cell survival, such as sugars,

OLIGOPEPTIDE TRANSPORTERS

The H+/peptide cotransporter (PEPT) 1 (SLC15A1)10,11 and PEPT2 (SLC15A2)12 mediate transport of dipeptides and tripeptides across plasma membranes into cells with the aid of an inwardly directed H+ gradient. PEPT1 generally has lower affinity and higher capacity than PEPT2 for substrate oligopeptides, and is functionally expressed in epithelial cells of the small intestine,13 bile duct, and kidney. PEPT1 predominantly contributes to intestinal absorption and renal reabsorption of various types

AMINO ACID TRANSPORTERS

Transport of amino acids across the plasma membrane is tightly controlled by and dependent upon amino acid transport systems that differ in structure, mechanism, and substrate specificity (reviewed in Ref. 87). There is compelling evidence, accumulated over the past two decades, that amino acid availability regulates cellular physiology by modulating gene expression as well as signal transduction pathways in cancer cells. Tumor cells compete with the host for circulating Gln, which is the major

Organic Cation Transporters

Polyspecific organic cation transporters (OCTs) consist of three isoforms (OCT1/SLC22A1, OCT2/SLC22A2, and OCT3/SLC22A3) and mediate bidirectional transport of various organic cations, including monoamine neurotransmitters, choline, and xenobiotics, as well as drugs. OCT1 and OCT2 are found in the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells, whereas OCT3 is distributed more ubiquitously and is considered to be the major component of the extraneuronal

ORGANIC ANION TRANSPORTING POLYPEPTIDES

Organic anion transporting polypeptides (OATPs) are currently classified into the SLCO superfamily.168 We first identified human cDNAs encoding OATPs that affect drug pharmacokinetics, and reported their expression in human cancer cell lines.169 Members of this family generally mediate Na+-independent transport of amphipathic organic anion compounds, including bile salts, steroid conjugates, thyroid hormones, and oligopeptides, as well as numerous drugs and xenobiotics, and recent progress in

OATP1B1

OATP1B1 was originally isolated in human liver169,172 and named LST1, based on its exclusive expression in the liver.172 It was characterized as an influx transporter for endogenous substances, including conjugated steroids [e.g., dehydroepiandrosterone sulfate (DHEAS),173 estradiol-17β-glucuronide (E17βG), and estrone-3-sulfate (E3S)],174 eicosanoids (e.g., prostaglandin E2), and thyroid hormones, as well as xenobiotics and many drugs used for chemotherapy. We first noticed that OATP1B1 is

OATP1B3

OATP1B3 (LST2/OATP8/SLCO1B3) has been shown to be differentially upregulated in human cancer cells since it was first isolated from human liver.49 OATP1B3 has been characterized as an influx transporter for bile acids and hormone conjugates including E17bG, E3S,174 and DHEAS.177 Recently, OATP1B3 was also reported to transport active steroid hormone such as testosterone,178 so that enhanced expression of OATP1B3 has been suggested as a prognostic factor in prostate cancer. In addition to

CONCLUSION

It is essential to specifically deliver anticancer drugs to tumor cells in order to increase clinical efficiency and reduce the side effects of anticancer agents. The effectiveness of cancer chemotherapy is often dependent on the relative transport capacities of normal and cancer cells. Cancer cells are capable of altering their genotype in an adaptive response to maximally utilize the nutriome of the host. It is therefore of clinical and pharmacological importance to investigate alterations of

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