The Oncologist, Vol. 4, No. 5, 428-429,
October 1999
© 1999 AlphaMed Press
Fundamentals of Cancer Medicine |
The Molecular Perspective: The Multidrug Transporter
David S. Goodsell
The Scripps Research Institute, La Jolla, California, USA
Correspondence:
David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu WorldWideWeb: http://www.scripps.edu/pub/goodsell
Oncologists are the greatest danger facing a typical cancer cell today. Cancer cells must survive surgical removal, exposure to lethal radiation, and poisoning by a plethora of chemotherapeutic drugs. But cancer cells are not passive targets—like all living things, they fight back. Cancer cells, since they are derived from normal human cells, have access to many of our natural defensive strategies. They pirate our normal defenses, using them against us to fight the challenges posed by modern medicine.
The multidrug transporter, or P-glycoprotein, is one defensive mechanism that has been forced into use for the defense of cancer cells. The transporter evolved to protect our cells from xenobiotic ("strange biological") substances. It is found immersed in the cell membrane, where it searches out and ejects these dangerous molecules. The transporter is normally found in several key places in the body: in cells lining the digestive tract, where it reduces absorption of toxic compounds in the diet; in the kidney and liver, where it aids in the excretion of these compounds; and in cells lining capillaries in the brain, forming one line of defense in the blood-brain barrier.
In tumor cells, the multidrug transporter provides resistance, and cross-resistance, to chemotherapeutic drugs. When treated, cancer cells express higher levels of the multidrug transporter, increasing the efficiency by which the drugs are ejected from the cell. The transporter is fairly promiscuous, acting on a wide variety of drugs, as shown in Figure 1 , so the resistance provided by the transporter against one drug will simultaneously confer cross-resistance against a wide range of other drugs. Biochemical results suggest that the transporter never allows these molecules to enter the cell at all. Instead, the toxic molecules are swept up while they are still in the membrane, and forcibly ejected under the power of ATP hydrolysis.
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Figure 1. Drugs that are transported. The xenobiotic molecules transported by the multidrug transporter share a few simple characteristics: they are lipophilic, so they tend to enter cells by passive diffusion through membranes, and they tend to have several polar groups, perhaps providing ready handles for recognition. Examples include many anticancer drugs, such as the vinca alkaloid vinblastine (upper left), paclitaxel (taxol, upper right), actinomycin D, many anthracylines, and mitomycin C. Other toxic compounds, such as colchicine (lower left), HIV protease inhibitors, gramacidin D, and ethidium bromide, are also transported. Verapamil (lower right) is an example of a chemosensitizer, which binds to the multidrug transporter and blocks its action, making the cell more susceptible to attack by drugs.
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The fight against cancer has escalated, and we must now look for new weapons. We have challenged cancer cells with chemotherapy, and they have responded by mobilizing our own multidrug transporter in their defense. The next step in the battle, now under study, is to use a chemosensitizer along with chemotherapy. Chemosensitizers are themselves non-toxic to cells, but block the action of the transporter, making the cells more sensitive to toxic molecules. Unfortunately, chemosensitizers sensitize both cancer cells and normal cells, increasing the effectiveness of the drugs against tumors, but also increasing their toxicity against healthy cells. Much of modern medicine is focused on similar battles: bacteria exchange information on resistance, forcing us to develop new antibiotics, and HIV uses artificially enhanced evolution to foil each new compound in turn. These tiny adversaries pit all of the resilience of life against our best rational therapies.
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Figure 2. The multidrug transporter. Electron micrograph reconstructions provide a tantalizing view of the multidrug transporter. The transporter is shown here in red spanning the membrane of an intestinal cell microvillus. The cell membrane runs vertically to the right of center, with the interior of the cell, filled with cross-linked actin fibers, on the left side, and the intestinal lumen on the right. The transporter is cup shaped, floating in the membrane with its opening facing right towards the exterior of the cell. There is a large hole in the side of the cup, which is buried within the membrane. One might imagine the transporter capturing individual drugs (the small orange molecules) within this hole, and then ejecting them outward through the large opening.
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Additional Reading
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 Top
 Additional Reading
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- Ambudkar SV, Dey S, Hrycyna CA et al. Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999;39:361-398.
- Rosenberg MF, Callaghan R, Ford RC et al. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 1997;272:10685-10694.
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