Drug transporters as targets for cancer chemotherapy.

Transporter proteins play an important role in taking up nutrients into and effluxing xenobiotics out of cells to sustain cell survival. Transporters that affect drug absorption, distribution and excretion are the so-called drug transporters. In the last decade, a number of studies revealed interactions between drug transporters and clinically important anticancer agents. Utilizing the knowledge of transporter functions offers us the possibility of delivering a drug to the target tissues, avoiding distribution to other tissues and improving oral bioavailability. Many transporters have been reported to be differentially up-regulated in cancer cells compared to normal tissues, suggesting that the differential expression of transporters in cancer cells may provide good targets for enhancing drug delivery as well as diagnostic markers for cancer therapy. This review will focus on the role of drug transporters in the adaptation and growth of tumors and in their potential usefulness as therapeutic targets in cancer. Approximately 4% of the genes in the human genome encode transporter proteins, including ion channels (1). Plasma membrane transporter proteins are encoded by numerous gene families. They are key players in the uptake of nutrients, such as sugars, amino acids, nucleosides and inorganic ions, into and the efflux of xenobiotic toxins, including many anticancer drugs out of cells to sustain cell survival. Transporter proteins can be classified into two major families, the solute carrier (SLC) and the ATP- binding cassette (ABC) transporters. Most ABC proteins transport a substrate molecule by utilizing the energy generated from ATP hydrolysis, while some form specific membrane channels. SLC transporters comprise both facilitated and secondary active transporters. Facilitated transporters move a molecule across plasma membranes following its concentration gradient, whereas secondary active transporters utilize the downhill flow of an ion to transport another molecule against its concentration gradient across the membranes in either the same (symport or cotransport) or opposite (antiport) direction. Currently the SLC and ABC family include 360 transporter genes in 46 subfamilies (2) and 48 transporter genes in 7 subfamilies (3, 4), respectively. Transporters that affect drug absorption, distribution and excretion are often called drug transporters, these confer sensitivity or resistance to anticancer drugs. The functional characterization of drug transporters provides important information crucial to drug design by targeting specific transporter proteins (5). The use of specific transporters as molecular targets in cancer therapy has been proposed as a promising strategy for tissue-selective drug delivery and for reducing systemic toxicity (6). More recent, transporter-targeted drug delivery approaches have been tested for their usefulness in the clinic. A number of studies revealed that many transporters are up-regulated in cancer cell lines and malignant tumors compared to normal tissues, suggesting that a differential expression of transporters in cancer exists and can be exploited for drug delivery or as diagnostic markers. This review will focus on the role of drug transporters for tumor growth and the usefulness of drug transporters as targets for specific drug delivery into cancer cells.