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Radical Reversal

Free radicals, widely believed to promote cancer, may actually slow tumor growth.

By | July 6, 2011

Pancreatic cancerWIKIMEDIA COMMONS, HELLERHOFF

Unstable molecules called reactive oxygen species (ROS) have long been thought to promote cancer by causing DNA damage and activating oncogenes, but new data suggests they may actually suppress tumor growth, according to a paper published this week in Nature.

The finding suggests that antioxidants, which clear ROS from a cell and are used as a treatment for cancer, may be doing more harm than good—causing complications instead of preventing disease.

“This is an outstanding and really interesting study that further suggests a duplicitous role for ROS in tumorigenesis,” Zachary Schafer, a cancer biologist at the University of Notre Dame, in an email. In 2009, Schafer demonstrated that eliminating ROS helps tumor cells survive outside their extracellular matrix. Similarly, the new data add to a growing body of literature that challenges the central dogma that antioxidants are always anti-tumorigenic, he said, acting to remove the carcinogenic ROS from tumor cells.

Still, the researchers looked at a transcription factor known to regulate ROS clearance, and that transcription factor has many other important functions that could be affecting the survival of tumor cells, said John Hayes, who studies cancer and antioxidants at the University of Dundee in Scotland and was not involved in the study, in an email. ROS’ tumor-suppressing role has yet to be directly demonstrated.

Previous studies suggest that cancer cells accumulate more ROS than normal cells do, and increasing levels of ROS in cancer cells has been viewed as a bad thing, promoting DNA damage, genetic instability and drug resistance in cells. Yet clinical trials for antioxidants like beta-carotene and vitamin E, which remove ROS and prevent free radical damage, have provided mixed results, some even causing an increase in cancer.

At the Cancer Research UK Cambridge Research Institute, David Tuveson and colleagues noticed that pancreatic cancer cells appeared to be very resistant to stress, and traced this robustness to low levels of ROS in the cells relative to normal cells.

The team investigated by examining a known cellular antioxidant program run by the transcription factor Nrf2, which lowers intracellular ROS, and its suppressor protein, Keap1. They found that three major oncogenes, Kras, Braf and Myc, expressed across a variety of human cancers, increased levels of Nrf2 in tumor cells. This increase in Nrf2 actively lowered intracellular ROS, clearing the cells of free radicals.

“We had expected that oncogenes would cause ROS,” not get rid of them, said Tuveson. So the team double-checked by blocking Nrf2 in mouse models of pancreatic and lung cancer, using genetic and pharmacological means. Consistent with their earlier finding, the loss of Nrf2 led to small, early tumors that didn’t progress. “We found that Nrf2 pathway is important for oncogenes to be fully functional,” said Tuveson.

Vitamin E, an antioxidant
Vitamin E, an antioxidant
WIKIMEDIA COMMONS, TAMORLAN

The surprising result suggests cancer cells can’t grow without Nrf2 suppressing ROS production. It’s possible, therefore, that medicines or vitamins people use in an effort to prevent cancer might actually help keep cancer cells alive. The finding may explain the failed, even harmful clinical trials for antioxidants. “There’s been no understanding of those trials at a molecular level,” said Tuveson. “We now have a potentially new scientific hypothesis to investigate [how ROS and antioxidants] relate to preventing cancer.”

Nrf2, however, also directs the transcription of numerous other pathways in cells, so its influence on ROS may not be the whole story. “Nrf2 regulates a battery of about 100 genes that have other functions,” said Hayes. For example, Nrf2 exerts a robust anti-inflammatory effect, which may be pivotal in allowing tumor cells to survive, he added. Thus, decreased ROS may not be the most important effect of Nrf2’s role in tumor cell survival.

Tuveson’s team plans to investigate that possibility next, exploring which parts of the Nrf2 pathway are the most important in promoting tumors.

G.M. DeNicola, et al., “Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis,” Nature, 475:106-9, 2011.

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Comments

Avatar of: Tom Hennessy

Tom Hennessy

Posts: 1457

July 7, 2011

If one looks at the 'discovery' this 'newly recognized process' is really nothing new. It seems to be just another bit of work in a long line of those in the 'pursuit to be published'. Case in point being grapefruit juice and its' warning label of not to be ingested with certain drugs. Seems the grapefruit juice is allowing one to use one third of the drug and therefore cutting into the profits of someone somewhere.
"Grapefruit Juice Boosts Drug's Anti- Cancer Effects"
"Results from a small, early clinical trial show that combininggrapefruit juice with the drug rapamycin can be effective in treatingvarious types of cancer. The grapefruit juice increases drug levels,allowing lower doses of the drug to be given."

Avatar of: Touscents

Anonymous

July 7, 2011

Do grapefruits have anti-oxidants?

Avatar of: Prince82

Anonymous

July 7, 2011

why certainly!

Avatar of: Stressdoc48

Anonymous

July 7, 2011

1) this study has never been published 2) all grapefruit juice did is increase the uptake of the drugs  3) warning about grapefruit have to do with the fact that is should not be take simultaneously with certain drugs, not to avoid it. It is possible that it was an artefact, because grapefruit juice inhibits CYP3A4 which metabolizes the drug, leading to increased serum levels. The response was not too great anyway..the drug was still cytostatic and not cytotoxic. An, this has nothing to do with the issues addressed in the Nature paper..

Avatar of: CAnswerMan

Anonymous

July 7, 2011

Utter nonsense. Oxidative stress is a well-known and demonstrated culprit in tumorigenesis.

Avatar of: Stressdoc48

Anonymous

July 7, 2011

i don't think Nature publishes utter nonsense...and all the notions about oxidative stress causing cancer are based on correlations..for example, as far as I know, no one has shown that knock-out of antioxidants leads to increased cancer and reversed such a process by feeding the mice antioxidats. Most of such knockouts are embryonic lethals, which could be argued that upsetting the balace of oxidants and  antioxidats are crucial for biological processes

Avatar of: Skeleben

Anonymous

July 7, 2011

I think there is some confusion caused by conflating cancer prevention with cancer treatment. It would make sense that reducing oxidative stress BEFORE tumorigenesis would be a good prophylactic against cancer. However, as highlighted in this article, once a cell has become metabolically dysregulated on the path to cancer, then you would expect the increased damage to selectively kill cancer cells. Unless, of course, the mutations act to increase expression of a ROS scavenger, such as Nrf2, in which case you get a more stable cancerous cell that may proceed on to tumorigenesis. By introducing ROS scavengers artificially, we would be taking care of the need for such a mutation, which provides a clear path for the cancer cell to continue propagating

Avatar of: Stressdoc48

Anonymous

July 7, 2011

this is a good point .. however 1) how do we  identify the metabolically dysregulated cell which will become a tumor ? there is excellent evidence that tumors have a single cell origin 2) the wide spread overdosing on antioxidants may not be as good as everyone assumes...

Avatar of: A Biochemist

Anonymous

July 7, 2011

Totally agree with previous comments. The results are easily predictable.
Another example - radiation can cause cancer, but is used to kill cancer cells.

Avatar of: Stressdoc48

Anonymous

July 7, 2011

Sorry, but I think you are missing the point..the mechanism by which radiation causes cancer is by inducing DNA damage that is not repaired, the way that it kills cells is by DNA damage that is not repaired.  ( I do research on this).The doses are different, but the process is the same. What this paper demonstrates than inhibition of oxidative stress in a tumor may lead to its growth..it is just an animal model. The point is that there is a balance of oxidants and antioxidants in the cell. Thus it MAY not be wise to take large doses of antioxidants indiscriminately.

Avatar of:

Posts: 0

July 7, 2011

If one looks at the 'discovery' this 'newly recognized process' is really nothing new. It seems to be just another bit of work in a long line of those in the 'pursuit to be published'. Case in point being grapefruit juice and its' warning label of not to be ingested with certain drugs. Seems the grapefruit juice is allowing one to use one third of the drug and therefore cutting into the profits of someone somewhere.
"Grapefruit Juice Boosts Drug's Anti- Cancer Effects"
"Results from a small, early clinical trial show that combininggrapefruit juice with the drug rapamycin can be effective in treatingvarious types of cancer. The grapefruit juice increases drug levels,allowing lower doses of the drug to be given."

Avatar of:

Posts: 0

July 7, 2011

Do grapefruits have anti-oxidants?

Avatar of:

Posts: 0

July 7, 2011

why certainly!

Avatar of:

Posts: 0

July 7, 2011

1) this study has never been published 2) all grapefruit juice did is increase the uptake of the drugs  3) warning about grapefruit have to do with the fact that is should not be take simultaneously with certain drugs, not to avoid it. It is possible that it was an artefact, because grapefruit juice inhibits CYP3A4 which metabolizes the drug, leading to increased serum levels. The response was not too great anyway..the drug was still cytostatic and not cytotoxic. An, this has nothing to do with the issues addressed in the Nature paper..

Avatar of:

Posts: 0

July 7, 2011

Utter nonsense. Oxidative stress is a well-known and demonstrated culprit in tumorigenesis.

Avatar of:

Posts: 0

July 7, 2011

i don't think Nature publishes utter nonsense...and all the notions about oxidative stress causing cancer are based on correlations..for example, as far as I know, no one has shown that knock-out of antioxidants leads to increased cancer and reversed such a process by feeding the mice antioxidats. Most of such knockouts are embryonic lethals, which could be argued that upsetting the balace of oxidants and  antioxidats are crucial for biological processes

Avatar of:

Posts: 0

July 7, 2011

I think there is some confusion caused by conflating cancer prevention with cancer treatment. It would make sense that reducing oxidative stress BEFORE tumorigenesis would be a good prophylactic against cancer. However, as highlighted in this article, once a cell has become metabolically dysregulated on the path to cancer, then you would expect the increased damage to selectively kill cancer cells. Unless, of course, the mutations act to increase expression of a ROS scavenger, such as Nrf2, in which case you get a more stable cancerous cell that may proceed on to tumorigenesis. By introducing ROS scavengers artificially, we would be taking care of the need for such a mutation, which provides a clear path for the cancer cell to continue propagating

Avatar of:

Posts: 0

July 7, 2011

this is a good point .. however 1) how do we  identify the metabolically dysregulated cell which will become a tumor ? there is excellent evidence that tumors have a single cell origin 2) the wide spread overdosing on antioxidants may not be as good as everyone assumes...

Avatar of:

Posts: 0

July 7, 2011

Totally agree with previous comments. The results are easily predictable.
Another example - radiation can cause cancer, but is used to kill cancer cells.

Avatar of:

Posts: 0

July 7, 2011

Sorry, but I think you are missing the point..the mechanism by which radiation causes cancer is by inducing DNA damage that is not repaired, the way that it kills cells is by DNA damage that is not repaired.  ( I do research on this).The doses are different, but the process is the same. What this paper demonstrates than inhibition of oxidative stress in a tumor may lead to its growth..it is just an animal model. The point is that there is a balance of oxidants and antioxidants in the cell. Thus it MAY not be wise to take large doses of antioxidants indiscriminately.

Avatar of:

Posts: 0

July 7, 2011

If one looks at the 'discovery' this 'newly recognized process' is really nothing new. It seems to be just another bit of work in a long line of those in the 'pursuit to be published'. Case in point being grapefruit juice and its' warning label of not to be ingested with certain drugs. Seems the grapefruit juice is allowing one to use one third of the drug and therefore cutting into the profits of someone somewhere.
"Grapefruit Juice Boosts Drug's Anti- Cancer Effects"
"Results from a small, early clinical trial show that combininggrapefruit juice with the drug rapamycin can be effective in treatingvarious types of cancer. The grapefruit juice increases drug levels,allowing lower doses of the drug to be given."

Avatar of:

Posts: 0

July 7, 2011

Do grapefruits have anti-oxidants?

Avatar of:

Posts: 0

July 7, 2011

why certainly!

Avatar of:

Posts: 0

July 7, 2011

1) this study has never been published 2) all grapefruit juice did is increase the uptake of the drugs  3) warning about grapefruit have to do with the fact that is should not be take simultaneously with certain drugs, not to avoid it. It is possible that it was an artefact, because grapefruit juice inhibits CYP3A4 which metabolizes the drug, leading to increased serum levels. The response was not too great anyway..the drug was still cytostatic and not cytotoxic. An, this has nothing to do with the issues addressed in the Nature paper..

Avatar of:

Posts: 0

July 7, 2011

Utter nonsense. Oxidative stress is a well-known and demonstrated culprit in tumorigenesis.

Avatar of:

Posts: 0

July 7, 2011

i don't think Nature publishes utter nonsense...and all the notions about oxidative stress causing cancer are based on correlations..for example, as far as I know, no one has shown that knock-out of antioxidants leads to increased cancer and reversed such a process by feeding the mice antioxidats. Most of such knockouts are embryonic lethals, which could be argued that upsetting the balace of oxidants and  antioxidats are crucial for biological processes

Avatar of:

Posts: 0

July 7, 2011

I think there is some confusion caused by conflating cancer prevention with cancer treatment. It would make sense that reducing oxidative stress BEFORE tumorigenesis would be a good prophylactic against cancer. However, as highlighted in this article, once a cell has become metabolically dysregulated on the path to cancer, then you would expect the increased damage to selectively kill cancer cells. Unless, of course, the mutations act to increase expression of a ROS scavenger, such as Nrf2, in which case you get a more stable cancerous cell that may proceed on to tumorigenesis. By introducing ROS scavengers artificially, we would be taking care of the need for such a mutation, which provides a clear path for the cancer cell to continue propagating

Avatar of:

Posts: 0

July 7, 2011

this is a good point .. however 1) how do we  identify the metabolically dysregulated cell which will become a tumor ? there is excellent evidence that tumors have a single cell origin 2) the wide spread overdosing on antioxidants may not be as good as everyone assumes...

Avatar of:

Posts: 0

July 7, 2011

Totally agree with previous comments. The results are easily predictable.
Another example - radiation can cause cancer, but is used to kill cancer cells.

Avatar of:

Posts: 0

July 7, 2011

Sorry, but I think you are missing the point..the mechanism by which radiation causes cancer is by inducing DNA damage that is not repaired, the way that it kills cells is by DNA damage that is not repaired.  ( I do research on this).The doses are different, but the process is the same. What this paper demonstrates than inhibition of oxidative stress in a tumor may lead to its growth..it is just an animal model. The point is that there is a balance of oxidants and antioxidants in the cell. Thus it MAY not be wise to take large doses of antioxidants indiscriminately.

Avatar of:

Posts: 0

July 8, 2011

In other words, moderation. But then how does one determine the right dosage of antioxidants when one is battling cancer? Is it wise to depend on the RDA indicated on the suppelement facts? I ask because MDs are not likely to "know" because in the first place they don't prescribe (normally) such.

Avatar of:

Posts: 0

July 8, 2011

I believe that maybe ross in cancer cells is a body defense, but if we use antioxidants to avoid DNA damages we could prevent cancer.

Avatar of:

Posts: 0

July 8, 2011

If you have a computer you could help this research group   http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 8, 2011

well crap! guess i should lay off the blueberries ;)

Avatar of:

Posts: 0

July 8, 2011

check out this research group   research you can do on your computer     http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 8, 2011

I agree with you.

Avatar of:

Posts: 0

July 8, 2011

In other words, moderation. But then how does one determine the right dosage of antioxidants when one is battling cancer? Is it wise to depend on the RDA indicated on the suppelement facts? I ask because MDs are not likely to "know" because in the first place they don't prescribe (normally) such.

Avatar of:

Posts: 0

July 8, 2011

I believe that maybe ross in cancer cells is a body defense, but if we use antioxidants to avoid DNA damages we could prevent cancer.

Avatar of:

Posts: 0

July 8, 2011

If you have a computer you could help this research group   http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 8, 2011

well crap! guess i should lay off the blueberries ;)

Avatar of:

Posts: 0

July 8, 2011

check out this research group   research you can do on your computer     http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 8, 2011

I agree with you.

Avatar of: TruthSeeker

Anonymous

July 8, 2011

In other words, moderation. But then how does one determine the right dosage of antioxidants when one is battling cancer? Is it wise to depend on the RDA indicated on the suppelement facts? I ask because MDs are not likely to "know" because in the first place they don't prescribe (normally) such.

Avatar of: Marielza

Anonymous

July 8, 2011

I believe that maybe ross in cancer cells is a body defense, but if we use antioxidants to avoid DNA damages we could prevent cancer.

Avatar of: help find a cure

Anonymous

July 8, 2011

If you have a computer you could help this research group   http://boinc.bakerlab.org/rose...

Avatar of: Jenn Murray

Jenn Murray

Posts: 1457

July 8, 2011

well crap! guess i should lay off the blueberries ;)

Avatar of: Ihatesnow100

Anonymous

July 8, 2011

check out this research group   research you can do on your computer     http://boinc.bakerlab.org/rose...

Avatar of: Marielza

Anonymous

July 8, 2011

I agree with you.

Avatar of: Charles Colenaty

Anonymous

July 11, 2011

Megan,
Fascinating article.  I read it twice, and will be reading it again.  However, I do need some help in understanding one portion of the article.  You make the statement,       "Previous studies suggest that cancer cells accumulate more ROS than normal cells."
Then in the following paragraph you say, "At the Cancer Research UK Cambridge Research Institute, David Tuveson
and colleagues noticed that pancreatic cancer cells appeared to be very
resistant to stress, and traced this robustness to low levels of ROS in
the cells relative to normal cells."

Am I to take it that pancreatic cancer cells differ froom other sorts of cancer cells in regard to content of ROS?

Avatar of: Ihatesnow

Anonymous

July 11, 2011

check out this research group           http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 11, 2011

Megan,
Fascinating article.  I read it twice, and will be reading it again.  However, I do need some help in understanding one portion of the article.  You make the statement,       "Previous studies suggest that cancer cells accumulate more ROS than normal cells."
Then in the following paragraph you say, "At the Cancer Research UK Cambridge Research Institute, David Tuveson
and colleagues noticed that pancreatic cancer cells appeared to be very
resistant to stress, and traced this robustness to low levels of ROS in
the cells relative to normal cells."

Am I to take it that pancreatic cancer cells differ froom other sorts of cancer cells in regard to content of ROS?

Avatar of:

Posts: 0

July 11, 2011

check out this research group           http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

July 11, 2011

Megan,
Fascinating article.  I read it twice, and will be reading it again.  However, I do need some help in understanding one portion of the article.  You make the statement,       "Previous studies suggest that cancer cells accumulate more ROS than normal cells."
Then in the following paragraph you say, "At the Cancer Research UK Cambridge Research Institute, David Tuveson
and colleagues noticed that pancreatic cancer cells appeared to be very
resistant to stress, and traced this robustness to low levels of ROS in
the cells relative to normal cells."

Am I to take it that pancreatic cancer cells differ froom other sorts of cancer cells in regard to content of ROS?

Avatar of:

Posts: 0

July 11, 2011

check out this research group           http://boinc.bakerlab.org/rose...

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