Sunday, 12 January 2014

Effect of Anti-Cancer Drugs Predicted By Autophagy : Cancer cells live or die?

It has been noted that when Cancer cells are treated with a particular dose of drug, some cells die while the other survive. For instance, on treating with IC-50 of a drug, 50% of cancer cells die while other 50% survive. Deputy director of the University of Colorado Cancer Center, Andrew Thorburn, PhD, answers this question in his new journal published in Nature Cell Biology: it is due to the variations in random autophagy in cells.

Autophagy is a process through which cell survives under the unfavourable conditions such as stress or deficiency by breaking down its non necessary components to provide energy to be used in degrading potentially harmful proteins. Hence, preventing any cellular damage. Thus cancer cells having low autophagy are more prone to death when treated with anti-cancer drugs than those that have low mortality due to high extent of autophagy. In his current study, Dr Andrew Thorburn shows that extent of autophagy and particular mechanism of anti-cancer drug are the two factors that influences the rates of cell death, either increasing or decreasing it.
According to Thorburn, cancer cells were separated into two different populations on the basis low and high autophagy respectively. These two populations were treated with death activating two drugs . On the action of first drug, cells with high autophagy had the highest mortality, while on treatment with the second drug, cells with low autophagy had the highest mortality. Thus, effect of autophagy was opposite depending on the drug.

Thorburn and his colleagues including Jacob Gump, PhD , treated both cell populations, low and high autophagy with two chemicals TRAIL and Fas ligand, which activate cells' death receptors. Cells treated with these chemicals die . Hence, some cells in both the populations underwent programmed cell death called apoptosis. It was observed that cells in population with high autophagy were more sensitive to chemical Fas ligand while cells in population with low autophagy were more sensitive to chemical TRAIL. Even in cancer cells, similar observations were noted as autophagy protects against these drugs in some cancer while in some , autophagy makes it more vulnerable.

In certain cancer cells, some but not all, a protein called FAP-1 is present whose major function is to prevent cell death by action of Fas Ligand. Groups showed that Autophagy degrades this FAP-1 protein when present in cells, making them more vulnerable to cell death by action of Fas ligand. Hence, how autophagy causes cell death in some tumors when treated with certain drugs is explained but not how it helps survival of other category of cells.

Moreover, Thorburn pointed out that cells in lab studies tend to be homogenous in their levels of autophagy compared to cells in natural tumor environments. It is likely, these laboratory results will be magnified in actual tumors, where levels of autophagy tend to vary more broadly.
While Fas ligand and TRAIL agonists are used in the lab only at this time. He further states that in future, further research will be done by performing  similar experiments with drugs that could be used in people.