P-glycoprotein

Image from RCSB Protein Data Bank (http://www.rcsb.org/pdb/101/motm.do?momID=123)

 

A crucial function of most of our cells is the maintenance of their internal environment. Processes that increase the concentration of products that may be lacking or inactivating things that have built up to a dangerous extent are termed homeostatic processes and occur continuously. The latter of these processes is the function carried out by Permeability Glycoprotein (P-glycoprotein).

In normal cellular conditions, P-glycoprotein functions as a surveillance protein, scanning the inside of cells for foreign or toxic compounds, binding to them and shifting them out before they can do any damage.

Like most of the proteins in our cells, their normal function can be manipulated to mediate the processes that occur in numerous diseases.

P-glycoprotein belongs to a class of proteins known as ‘ABC transporters’. These molecules have an intra-cellular portion that can recognise a huge range of both potentially harmful substances and normal proteins that need to be pumped out of cells. Once the substance has been bound, the pump undergoes a change in shape, referred to as a conformational change, allowing the potentially harmful protein to be shuttled across the cell membrane.

This process is utilised in numerous normal cellular functions, such as the removal of potentially toxic compounds from cells of the gastro-intestinal tract to be excreted and the protection of the brain, as part of the blood-brain barrier which prevents potentially harmful products in the bloodstream from gaining access to the brain.

However, like many proteins, P-glycoprotein can be exploited to have disease-promoting functions. The greatest challenge posed by this protein in disease settings is mediating resistance to chemotherapy. This transporter is thought to be aberrantly active in many cancers, indeed this is how P-glycoprotein was first discovered and characterised. In these cases, P-glycoprotein actively transports the chemotherapeutic agents out of the cancer cells before they can have their cell-killing function. Concerningly, a number of commonly used drugs are actively removed from cancer cells by this mechanism, including doxorubicin and etoposide.

Chemoresistance is a significant concern for clinicians, as it means they have to resort to using second-line agents that have significantly worse side-effects and may not as be effective as their preferred counter-parts. Therefore, blocking the processes that generate resistance is of great interest. Numerous potential mechanisms have been suggested, including both directly blocking the function of the protein and preventing its synthesis. Interestingly, it is thought that some well-known drugs may act to block these transporters. The anti-malarial drug Quinine, although no longer widely used, may have a clinical application to block P-glycoprotein and reduce the resistance of cancer cells to common therapeutics.

‘Til next time…

Joe

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