LONDON — Pharmacologists may soon be able to identify new drugs — both antibiotics and anticancer agents — which cannot be shrugged off by the cells they are supposed to kill.
This possibility arises following the discovery that there are remarkable similarities between the proteins which pump antibiotics out of bacteria and those which remove anticancer drugs from human cancer cells.
When someone with cancer receives chemotherapy, the tumor cells most likely to survive are those that overexpress a protein called P-glycoprotein. This protein, which is found in the cell membrane, pumps a broad range of anticancer drugs out of the cell. After several courses of treatment, any tumor remaining is likely to be resistant to several drugs, and the tumor is able to multiply without restraint.
Now a team of scientists based in the Netherlands and the U.K. has shown that P-glycoprotein is very similar in structure and function to a comparable protein found in the membrane of the bacterium Lactococcus lactis, called LmrA. This protein confers antibiotic resistance on the bacteria it is found in by removing drugs from the bacterial membrane and depositing them outside the cell.
Hendrik Van Veen, research scientist and project leader at the Groningen Biomolecular Sciences and Biotechnology Institute of the University of Groningen, in the Netherlands, and his colleagues reported their work in a letter to the Jan. 15 issue of Nature, titled "A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene."
The group took the gene for LmrA and expressed it in human lung fibroblast cells. To its surprise, it found the protein made by the bacterial gene appeared in the plasma membrane of the cell. The researchers then studied what happened when they added drugs such as doxorubicin, vinblastine, vincristine and colchicine, which can normally be pumped out of cells expressing P-glycoprotein.
Bacterial Membrane Protein Functions In Mammals
Although the genetically engineered cells contained undetectable levels of P-glycoprotein, the team found they were between 10 and 60 times more resistant than normal to the drugs added. Mock-transfected control cells showed no increase in resistance.
Van Veen told BioWorld International, "This suggests to us that the bacterial LmrA protein and the human multidrug resistance P-glycoprotein are functionally identical."
The researchers went on to see what would happen if they added compounds that normally inhibit the function of P-glycoprotein. They found these drugs could also reverse the drug resistance conferred by the presence of the LmrA protein.
"This was totally unexpected," said Van Veen. "For some reason this system has been conserved from bacteria to humans. This may be because cells have to defend themselves against toxic substances found in nature, or it may be to do with the transport of phospholipids or the excretion of signal molecules, both of which are amphiphilic, like all the drugs which P-glycoprotein is able to expel."
To their knowledge, this is the first time a prokaryotic membrane protein has been functionally expressed in mammalian cells, Van Veen and his co-authors wrote. "The correct sorting of LmrA to the plasma membrane in mammalian cells is surprising in itself," they added.
The result, Van Veen concluded, "is that we now have a drug pump in a bacterium that is very similar to that found in human cancer cells which are resistant to drug therapy. By studying the bacterial protein, we will find out more about the human drug pump and about the mechanism of antibiotic resistance in pathogenic microorganisms."
Next, the group plans to study the interaction between drugs and drug pumps in more detail. "It may be possible to design new drugs — both antibiotics and anticancer agents, which are not recognized by these pumps," Van Veen predicted.