Research Says Reduce-Not Increase Antioxidants to Kill Pancreatic Cancer Cells.

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Conventional wisdom in popular culture is to raise antioxidants in the body to facilitate recovery from cancer researchers have found that in pancreatic cancer the last thing one wants to do is raise antioxidants levels. Instead lowering antioxidants in pancreatic cancer cells can kill them them according to the researchers of the study published in  the journal Cell.  Pancreatic cancer is a lethal disease in which 5 per cent of the cases survive 5 years. /

In normal cells oxidizing and antioxidizing agents are created in every cell and kept in a precise balance. However, in proliferating cancer cells  more oxidizing cells are being made in malignant cells but more antioxidants are being made also that counter the impact of rising oxidation and without commensurately more antioxidants the  malignant cells will die due to excessive oxidation and that is what is desired. Researchers tested  whether by increasing the level of oxidation in cancer cells,the pre-cancerous cells and malignant cells would die. When cells detect excessive oxidation, they commit suicide, following a built in program called apoptosis and one way to increase oxidation in cancer cells is to decrease levels of antioxidants in those same cells.

Researchers were interested in how best to do this without harming normal cells. The focused on a protein called NRF2 which is considered a master regulator of redox homeostasis or by which they can turn the switch to tweak and disturb the exquisite balance between oxidation and reduction in cancer cells. When NRF2 is active, cells synthesize a chemical called glutathione that is an important antioxidant. Thus, by reducing NRF2 activity or knock it out of action would seem desirable but this is not possible for two reasons. First, it is a transcription factor—a protein that regulates the activities of other genes.  Transcription factors is famously difficult to target but researchers say that would not be desirable because in addition to promoting  production of glutathione, NFR2 has a role in regulating several hundred different gene that impact on many other processes.

After conducting experiments and testing pancreatic cells in animal models they arrived at a different strategy. They used a panel of pancreatic organoids,  spherical agglomerations of pancreatic cells, sampled from people with pancreatic cancer and from healthy pancreas and were able to observe what happens when NRF2 is completely eliminated. They ran the test on normal, premalignant and malignant pancreatic organoids. They saw that the premalignant organoids carried cellular mutations in the Kras gene that is aberrant in almost all human pancreatic cancers. The malignant organoidshad that mutation and also a mutation that inactivates the powerful tumor supressor gene P53 and these with Kras are seen in most human malignancies.

Researchers, thus, saw that when NRF2 is missing the mechanism in cells that translate messages from genes to proteins (protein synthesis) is very sensitive to fluctuations in the balance between oxidants and anti-oxidants. However, protein synthesis was not impacted in normal pancreatic cells. Researchers said “We were very excited when we saw this. This meant that if we could find a way of reducing antioxidants, protein synthesis would only be impacted in precancerous and malignant cells, a potentially powerful therapeutic strategy.”

Using a mouse model they found that using two drugs–one that inhibited the beginning of the translation process that leads to protein synthesis and the other inhibited the synthesis of glutathione which is an antioxidant- was more effective in killing cancer cells that either alone and normal pancreatic cells were not affected. Further research to look at combinations and to increase efficacy are planned.

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