Washington, Aug 19 : Researchers from Stanford University have come up with a new method to combat diseases that have developed multiple drug resistance.
The researchers revealed that using an arginine-rich transporter to ferry a potent medication inside a resistant cell would help restore the drug effectiveness.
Arginine is an amino acid, the building block of proteins, and as such is found in virtually every cell in the human body, as well as other mammalian bodies.
"Nature has developed all of this firepower for getting things into cells, and one of the ways is to create entities that are arginine-rich," said Paul Wender, the Bergstrom Professor of Chemistry at Stanford University.
"Arginine-rich sequences appear to figure in the mechanisms by which many pathogens invade cells," Wender added.
The team led by Wender discovered that a particular molecular subunit within arginine, called a guanidinium group, was what nature actually exploits to get foreign substances through cell membranes.
With the help of drug Taxol(r), a widely used chemotherapeutic agent, they attached a series of arginines with their associated guanidinium groups and tried it out against Taxol-resistant ovarian cancer cells implanted in mice. It helped improve drug resistance.
"It's an exciting result to be able to take a drug known to work against cancer, but stymied by resistant cells, and restore it to effectiveness using an arginine transporter. "This bodes well for use with other drugs that succumb to resistance," said Wender.
The type of drug resistance that Wender's team has overcome develops when pumps located in the membrane that encloses a cell become sensitized to a medication. It is one of the most common ways in which resistance manifests.
The pumps, which normally capture and eject foreign material from a cell, are produced at higher levels in certain resistant cells and, because of their increased number, become more effective at tossing the drug molecules out.
"It work's as a bouncer in cellular club," he said.
The team conducted further studies to see if they could take drugs to which diseases had become resistant and, by combining them with what they call "molecular transporters," get them in around the pump.
"If we think of the pump as being a bouncer for the cellular club, then effectively what we're doing is disguising one of these therapeutic agents to get it in through the back door or the side door," Wender said. "We're not even going to deal with the bouncer."
The basic approach of bonding a medication to an arginine-rich transporter to slip it past the cellular sentries could, in theory, be used to get any of a host of medications into any cell that has developed the type of resistance involving increased numbers of export pumps. That could include medications for diseases caused by antibiotic resistant bacteria, such as multi-drug resistant tuberculosis, or by drug resistant parasites such as malaria, as well as other types of cancer.
The arginine transporter manages to avoid ejection by slipping through the membrane of the cell in between the pumps.
"As the transporter, with all these arginine guanidinium groups, approaches the cell, it basically does a handshake using hydrogen bonds with cell surface constituents that are in the membrane," Wender said. "In essence, it changes its physical properties by shaking hands with all these cell membrane components."
That change in physical properties effectively cloaks the arginine-Taxol complex, allowing it to slip past the sentries and into the cell. As it passes into the cell, the weak bonds it formed with the membrane components break and the transporter, with its therapeutic load, is free to roam inside the cell.
To its job against cancer cells, arginine-Taxol complex break apart with the help of molecule called glutathione.
The researchers achieved another breakthrough by tinkering with the form of the arginine used in their transporter. By altering certain aspects of the arginine, the researchers were able to control the rate at which glutathione slices and dices the arginine-Taxol complex.
This gives them an unprecedented ability to regulate the amount of medication that is active inside the patient at any point in time.
The paper will be published next week in the online Early Edition of the Proceedings of the National Academy of Sciences.