They also led to a method to regulate the amount of medication that is active, according to paper in PNAS.
A group of researchers have found that Taxol can be restored to effectiveness in mice who had developed a resistance to the drug by using an arginine transporter.
The researchers also deviced a way to regulate the amount of medication that is active inside the patient at any point in time. They altered certain aspects of the arginine and were thus able to control the rate at which glutathione breaks down the arginine-Taxol complex.
The scientists figured out that a particular molecular subunit within arginine, called a guanidinium group, was what nature actually exploits to get foreign substances through cell membranes. They attached eight arginine molecules with their associated guanidinium groups around Taxol.
The team focused on resistance that develops when pumps located in the membrane that encloses a cell become sensitized to a medication. The pumps, which normally capture and eject foreign material from a cell, get produced at higher levels in certain resistant cells. With this increase, they become more effective at tossing out drug molecules as well.
The arginine transporter manages to avoid ejection by slipping through the membrane of the cell in between the pumps. The key is the ability of arginine to form weak, temporary bonds with some of the molecules that reside in the membrane.
That change in physical properties effectively cloaks the arginine-Taxol complex. After getting into the cell, however, the complex still has to break apart for the Taxol to do its job against the cancer cell. The researchers achieved this by taking advantage of the presence of a molecule called glutathione, which is generally abundant inside cells and which in cancer cells, tends to be present in higher levels than usual. Glutathione is predisposed to attacking sulphur-sulphur bonds, so that is the bond the researchers used to hold the arginine and Taxol together.
Because glutathione is relatively scarce outside of cells, the arginine transporter is effectively inert in that environment, so there are no side effects from having the arginine-Taxol complex moving through the patient’s body.
Scientists from Stanford University, the University of California-Berkeley, and the University of Pittsburgh conducted this research. A paper describing the work is scheduled to be published next week in the online early edition of the Proceedings of the National Academy of Sciences.