What is PGP? Human p-glycoprotein, (Pgp), is a transmembrane pump protein. Structurally, Pgp is a member of a family of proteins called the ATP-binding cassette (ABC) superfamily. Like the other members of this family, Pgp is composed of two homologous subunits, each of which are composed of 6 transmembrane domains (TMD). The ATP-binding domain (NBD) of each subunit is separated by a linker polypeptide (Figure 1).

Figure 1

What does PGP do? Pgp uses energy obtained from hydrolyzing the high-energy phosphate bonds of ATP to actively pump toxic hydrophobic compounds across the plasma membrane (Figure 2). Normal mammalian tissue contains active Pgp, particularly in the epithelial cells surrounding the brain, intestine, adrenal gland and testis. Each of these tissues is markedly sensitive to environmental toxins, and Pgp appears to be an important component of the barrier which protects such tissues from potentially harmful substances.

Figure 2

The problem with Pgp. Although properly functioning Pgp protects the cell from toxins, its action can become a grave liability for patients suffering from the ravages of cancer. Standard chemotherapy treatment regimens for cancer typically involve highly toxic chemicals designed to kill tumor cells. Unfortunately, while such drug cocktails are needed to effectively combat the rogue cells of a tumor, Pgp can not distinguish between common environmental toxins and the harmful chemicals used to treat disease. In the phenomenon known as multi-drug resistance (MDR), tumor cells will use Pgp to pump out therapeutic medication before it can penetrate the tumor and effectively eliminate the cancer. (Figure 3)

Figure 3

Multi Drug Resistance (MDR) MDR is a clinical phenomenon in which cells become resistant to a range of different chemicals, all of which are toxic in normal cells. MDR presents a particular problem for oncologists attempting to treat cancer with chemotherapy. Tumors exposed to anti-cancer agents tend to develop resistance to not only the particular drugs being used, but also to many other chemicals to which they have never been exposed. This additional resistance eliminates chemotherapy as an effective cancer treatment for such tumors. In addition, some forms of MDR are known to be heritable in successive generations of tumor cells. This suggests a possible mechanism for MDR involving the alteration of transcription and gene expression.

Why study Pgp? The study of Pgp structure, function, and inhibition are active areas of biomedical reasearch because of their potential to improve the utility of chemotherapy. However, in a surprising twist, the more that is discovered about Pgp, the more wide-ranging its effects appear to be. In addition to its role in cancer biology, Pgp is also involved in controlling apoptosis and ion channel activation. As a result of its multi-faceted role in the cell, understanding what Pgp does and how it does it are important research goals.