Chemotherapy is the treatment of cancer but some cancers put up a fight against regular treatments such as chemotherapy or radiotherapy due to their various "strategies" for survival. But by manipulating cellular processes, scientists have now found a way of bypassing one of cancer's self preservation mechanisms.
            

Generally ‘cancer’ is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread to other parts of the body. Possible signs and symptoms include a lump, abnormal bleeding,prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they may have other causes. Over 100 types of cancers affect humans.


More than 30% of cancer deaths could be prevented by avoiding risk factors including: tobacco, excess weight/obesity, poor diet, physical inactivity, alcohol, sexually transmitted infections and air pollution. Not all environmental causes are controllable,such as naturally occurring background radiation and cancers caused through hereditary genetic disorders and thus are not preventable via personal behavior.


Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs (chemotherapeutic agents) as part of a standardized regimen. The term encompasses a variety of drugs, which are divided into broad categories such as alkylating agents and anti metabolites.Traditional chemotherapeutic agents act by killing cells that divide rapidly, a critical property of most cancer cells.

 

But some cancers put up a fight against regular treatments such as chemotherapy or radiotherapy due to their various "strategies" for survival. But by manipulating cellular processes, scientists have now found a way of bypassing one of cancer's self-preservation mechanisms.

 

Autophagy— a term meaning "self-devouring" in Greek — is, normally, cells' way of staying orderly and functional.


This is due to the fact that when autophagy is triggered, cells break down the elements that aren't useful any longer and "recycle" material for reuse.


This process has been shown to have complex implications for cancer cells; sometimes it helps to destroy them, but at other times it helps them to thrive. One way in which cancer cells use autophagy "in their own interest" is to evade apoptosis, or cell death.


Apoptosis and autophagy both rely on similar mechanisms to break down cellular material that is no longer helpful. But while apoptosis takes this disassembly all the way, eventually causing the cell to die, in autophagy, death is postponed by recycling some of the cellular material.

           

Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Autophagy protects against cancer by mediating both innate and adaptive immune responses.

            

In many cases, researchers have discovered that chemotherapy and radiotherapy can increase the presence of autophagy in cancer cells, which actually allows them to enter a "hiatus" mode that helps them to evade cell death and resume their activity later.


While researchers have studied the importance of autophagy inhibitors in promoting apoptosis, the underlying mechanisms that allow cell death to occur when this recycling process is inhibited have remained unclear.


Now, researchers from the University of Colorado Cancer Center in Aurora have begun to uncover some of these mechanisms, which has also allowed them to develop afresh strategy to bypass tumor cells' autophagy and trigger their death more efficiently.


The results of the study — which was led by Andrew Thorburn — have now been published in the journal Developmental Cell.

Increase ‘PUMA’ drives cell death

In the new study, the researchers explain that the so-far mysterious link between autophagy and apoptosis is transcription factor FOXO3a, which is a protein that carries with it "instructions" as to what should take place at cellular level.


"The problem," says Thorburn, "is this: many anti-cancer treatments push cancer cells to the brink of death. But the cells use autophagy to go into a kind of suspended animation, pausing but not dying."


"We don't want cancer cells to pause; we want them to die. We show that FOXO3a may make the difference between these two outcomes." Andrew Thorburn


Moreover it turns out that FOXO3a plays a key role in the cellular homeostasis related to autophagy — that is, it helps to regulate that process. Interestingly,though, autophagy also helps to regulate the levels of this transcription factor.


In other words, when the presence of autophagy is increased, FOXO3a levels go down, and when autophagy is down regulated, more FOXO3a is produced, thereby boosting the cellular recycling process. This means that autophagy remains at constant levels, sometimes despite the action of chemotherapy drugs.

           

Recent research reveals how we may be able to bypass one of cancer's survival strategies and trigger tumor cell death.

           

Previous research carried out at Thorburn's laboratory revealed that another protein — known as PUMA — is key in"telling" cells when to self-destruct. Now, Thorburn and team have also found that FOXO3a can increase the expression of the gene that drives the production of PUMA.


Long story short, when autophagy is inhibited, more FOXO3a is produced, and when that happens, the heightened levels of FOXO3a help boost the presence of autophagy in cancer cells again. But at the same time, the transcription factor increases the presence of PUMA, which drives cell death.

New mechanism needs a combination of therapy

Seeing the result of the discovery, the scientists were interested in studying whether they could use these mechanisms to render cancer cells more vulnerable to apoptosis. Their strategy involved using autophagy inhibitors alongside a tumor suppressing drug called Nutlin.


As the drug is known to stunt the growth of cancer cells, it had not been tied to triggering cell death. So, the researchers wanted to learn whether, by pairing it up with autophagy inhibitors, apoptosis would be prompted more efficiently.


Dr. Thorburn and colleagues decided to test both therapies in concert is because both autophagy inhibition and Nutlin are known to increase the production of PUMA, though they do so through independent channels: FOXO3a and a transcription factor known as p53, respectively.


"What we wanted to see," says first author Brent Fitzwalter, "is whether these two things together — Nutlin along with autophagy inhibition — would increase PUMA past the point of growth inhibition and into actual cell death."


By analyzing a series of tests conducted on cell cultures and mouse models of cancer tumors, the researchers were delighted to see that this strategy did work the way they hoped it would.


"The result was that we turned a drug that could slow down tumor growth but couldn't kill cancer cells into one that now kills the cells." Andrew Thorburn


The new findings, the researchers add, could provide the groundwork for future clinical trials putting this combination treatment to the test to confirm its effect.

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