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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 11, 2013

Reactive Oxygen Species Are Your Friends!

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Posted by Derek

The line under James Watson's name reads, of course, "Co-discoverer of DNA's structure. Nobel Prize". But it could also read "Provocateur", since he's been pretty good at that over the years. He seems to have the right personality for it - both The Double Helix (fancy new edition there) and its notorious follow-up volume Avoid Boring People illustrate the point. There are any number of people who've interacted with him over the years who can't stand the guy.

But it would be a simpler world if everyone that we found hard to take was wrong about everything, wouldn't it? I bring this up because Watson has published an article, again deliberately provocative, called "Oxidants, Antioxidants, and the Current Incurability of Metastatic Cancers". Here's the thesis:

The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies.

The article is interesting throughout, but can fairly be described as "rambling". He starts with details of the complexity of cancerous mutations, which is a topic that's come up around here several times (as it does wherever potential cancer therapies are discussed, at least by people with some idea of what they're talking about). Watson is paying particular attention here to mesenchymal tumors:

Resistance to gene-targeted anti-cancer drugs also comes about as a consequence of the radical changes in underlying patterns of gene expression that accompany the epithelial-to-mesenchymal cell transitions (EMTs) that cancer cells undergo when their surrounding environments become hypoxic [4]. EMTs generate free-floating mesenchymal cells whose flexible shapes and still high ATP-generating potential give them the capacity for amoeboid cell-like movements that let them metastasize to other body locations (brain, liver, lungs). Only when they have so moved do most cancers become truly life-threatening. . .

. . .Unfortunately, the inherently very large number of proteins whose expression goes either up or down as the mesenchymal cancer cells move out of quiescent states into the cell cycle makes it still very tricky to know, beyond the cytokines, what other driver proteins to focus on for drug development.

That it does. He makes the case (as have others) that Myc could be one of the most important protein targets - and notes (as have others!) that drug discovery efforts against the Myc pathway have run into many difficulties. There's a good amount of discussion about BRD4 compounds as a way to target Myc. Then he gets down to the title of the paper and starts talking about reactive oxygen species (ROS). Links in the section below added by me:

That elesclomol promotes apoptosis through ROS generation raises the question whether much more, if not most, programmed cell death caused by anti-cancer therapies is also ROS-induced. Long puzzling has been why the highly oxygen sensitive ‘hypoxia-inducible transcription factor’ HIF1α is inactivated by both the, until now thought very differently acting, ‘microtubule binding’ anti-cancer taxanes such as paclitaxel and the anti-cancer DNA intercalating topoisomerases such as topotecan or doxorubicin, as well as by frame-shifting mutagens such as acriflavine. All these seemingly unrelated facts finally make sense by postulating that not only does ionizing radiation produce apoptosis through ROS but also today's most effective anti-cancer chemotherapeutic agents as well as the most efficient frame-shifting mutagens induce apoptosis through generating the synthesis of ROS. That the taxane paclitaxel generates ROS through its binding to DNA became known from experiments showing that its relative effectiveness against cancer cell lines of widely different sensitivity is inversely correlated with their respective antioxidant capacity. A common ROS-mediated way through which almost all anti-cancer agents induce apoptosis explains why cancers that become resistant to chemotherapeutic control become equally resistant to ionizing radiotherapy. . .

. . .The fact that cancer cells largely driven by RAS and Myc are among the most difficult to treat may thus often be due to their high levels of ROS-destroying antioxidants. Whether their high antioxidative level totally explains the effective incurability of pancreatic cancer remains to be shown. The fact that late-stage cancers frequently have multiple copies of RAS and MYC oncogenes strongly hints that their general incurability more than occasionally arises from high antioxidant levels.

He adduces a number of other supporting evidence for this line of thought, and then he gets to the take-home message:

For as long as I have been focused on the understanding and curing of cancer (I taught a course on Cancer at Harvard in the autumn of 1959), well-intentioned individuals have been consuming antioxidative nutritional supplements as cancer preventatives if not actual therapies. The past, most prominent scientific proponent of their value was the great Caltech chemist, Linus Pauling, who near the end of his illustrious career wrote a book with Ewan Cameron in 1979, Cancer and Vitamin C, about vitamin C's great potential as an anti-cancer agent [52]. At the time of his death from prostate cancer in 1994, at the age of 93, Linus was taking 12 g of vitamin C every day. In light of the recent data strongly hinting that much of late-stage cancer's untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.

All in all, the by now vast number of nutritional intervention trials using the antioxidants β-carotene, vitamin A, vitamin C, vitamin E and selenium have shown no obvious effectiveness in preventing gastrointestinal cancer nor in lengthening mortality [53]. In fact, they seem to slightly shorten the lives of those who take them. Future data may, in fact, show that antioxidant use, particularly that of vitamin E, leads to a small number of cancers that would not have come into existence but for antioxidant supplementation. Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.

Now this is quite interesting. The first thing I thought of when I read this was the work on ROS in exercise. This showed that taking antioxidants appeared to cancel out the benefits of exercise, probably because reactive oxygen species are the intracellular signal that sets them off. Taken together, I think we need to seriously consider whether efforts to control ROS are, in fact, completely misguided. They are, perhaps, "essential poisons", without which our cellular metabolism loses its way.

Update: I should also note the work of Joan Brugge's lab in this area, blogged about here. Taken together, you'd really have to advise against cancer patients taking antioxidants, wouldn't you?

Watson ends up the article by suggesting, none too diplomatically, that much current cancer research is misguided:

The now much-touted genome-based personal cancer therapies may turn out to be much less important tools for future medicine than the newspapers of today lead us to hope [54]. Sending more government cancer monies towards innovative, anti-metastatic drug development to appropriate high-quality academic institutions would better use National Cancer Institute's (NCI) monies than the large sums spent now testing drugs for which we have little hope of true breakthroughs. The biggest obstacle today to moving forward effectively towards a true war against cancer may, in fact, come from the inherently conservative nature of today's cancer research establishments. They still are too closely wedded to moving forward with cocktails of drugs targeted against the growth promoting molecules (such as HER2, RAS, RAF, MEK, ERK, PI3K, AKT and mTOR) of signal transduction pathways instead of against Myc molecules that specifically promote the cell cycle.

He singles out the Cancer Genome Atlas project as an example of this sort of thing, saying that while he initially supported it, he no longer does. It will, he maintains, tend to find mostly cancer cell "drivers" as opposed to "vulnerabilities". He's more optimistic about a big RNAi screening effort that's underway at his own Cold Spring Harbor, although he admits that this enthusiasm is "far from universally shared".

We'll find out which is the more productive approach - I'm glad that they're all running, personally, because I don' think I know enough to bet it all on one color. If Watson is right, Pfizer might be the biggest beneficiary in the drug industry - if, and it's a big if, the RNAi screening unearths druggable targets. This is going to be a long-running story - I'm sure that we'll be coming back to it again and again. . .

Comments (21) + TrackBacks (0) | Category: Biological News | Cancer


COMMENTS

1. ScientistSailor on January 11, 2013 10:42 AM writes...

He's right that most cancer research is mis-guided. But without some concrete data, this seems like a classic example of the Narrative Fallacy.

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2. Algirdas on January 11, 2013 11:17 AM writes...

OT, but:

there used to be a convention that transverse sticks in a schematic drawing of DNA double helix represent base pairs. I note with interest that the drawing on a cover of "The Double Helix" amazon.com link from the post seems to have seventeen base pairs per half turn. Perhaps I'm just an old man clinging to conventions of the past.

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3. Boghog on January 11, 2013 11:32 AM writes...

I have always been partial to free radicals.

99u.com/articles/7098/A-Manifesto-For-Free-Radicals-Less-Paperwork-Less-Waiting-More-Action

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4. NoDrugsNoJobs on January 11, 2013 11:37 AM writes...

The antioxidant hypothesis of health/cancer/aging was always troubling because everything is an oxidant/antioxidant relative to something else. The subtleties of any biological pathology are so immense that to ask whether an oxidative or reductive environment is beneficial would need to depend on all the factors that the importance of any other biologically relevant chemical reaction is subject to. Except its innate simplistic appeal, the antioxidant theory of preventing aging/cancer, etc is as logical as an SN2 displacement theory of aging, that is if we can reduce (or increase or whatever) displacement reactions we can increase/decrease lifespan/cancer, etc. Essentially every antioxidant can be an oxidant as well, or its oxidized reaction product can be - so what does it mean to say something is an antioxidant? Relative to what? In what context?. Its impossible to say absent some very specific context where all of the corresponding factors are known and understood.

Further, it appears the good Doctor launches from one fallacy to the opposite - since antioxidants are not proven to be good and might even be harmful in some contexts, that it is a pro-oxidant environment which is then desiraeble. This would seem to be committing the same fallacy but on the other side.

I am still wondering when all the anti-oxidant vitamin and nutritional supplement ads will end. Hopefully not when the pro-oxidant ones begin! I wonder how long until the good Doctor starts his own pro-oxidant company?

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5. Chemjobber on January 11, 2013 11:57 AM writes...

#4: I was waiting for Watson to shift into "and that's why drinking dilute hydrogen peroxide is awesome!" It never came -- will wonders ever cease?

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6. Calvin on January 11, 2013 12:16 PM writes...

I must admit that I immediately thought of the ROS and exercise story too!

#4 You're right but my interpretation was that Watson wasn't proposing that we go all the way to a reducing environment but rather than preventing oxidation was flawed. I read that he was saying that oxidation was important and that we shouldn't try to block it with the assumption that that would fix everything. I assumed that he was inherently suggesting that returning the biological system to a more balanced oxidative state was desirable.

And I think he's got a very interesting point about metabolic pathways maybe being way more interesting than regulatory pathways. It's worth investigating further.

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7. antiaromatic on January 11, 2013 1:58 PM writes...

Am I missing something or is there a problem with his saying we have 24 chromosomes???

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8. ptm on January 11, 2013 2:01 PM writes...

I also find the view that oxidative stress is either all bad or all good to be pretty naive.

It's a bit like arguing whether high voltage is good or bad for electrical machines. Of course it all depends on particular application, some machines will be fried by it while others won't work without it. Any attempt to draw general conclusions is hopelessly misguided.

I bet the same applies to cellular oxidative potential - it's a tool employed by cells to achieve various goals.

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9. Anonymous on January 11, 2013 2:07 PM writes...

He makes a pretty big stretch here:

"In light of the recent data strongly hinting that much of late-stage cancer’s untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer"

I could buy a hypothesis that antioxidants could accelerate late-stage cancers, but CAUSE cancer? Pretty outrageous.

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10. drug_hunter on January 11, 2013 3:07 PM writes...

I do think that Watson is correct in focusing on myc. Of course it is (very) hard from a druggability perspective but I think that if we crack the chemical challenge there is a high chance for breakthrough cancer medicines.

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11. paperclip on January 11, 2013 3:09 PM writes...

@9 It may have been more accurate of him to write "*excessive* antioxidant use". For instance, in one study demonstrating that men taking vitamin E had increased prostate cancer risk, the supplement they were taking was 18 times the RDA.

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12. Jonathan on January 11, 2013 3:10 PM writes...

TBQH I'm amazed anyone still takes anything he says seriously.

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13. Anonymous on January 11, 2013 3:14 PM writes...

9: "I could buy a hypothesis that antioxidants could accelerate late-stage cancers, but CAUSE cancer? Pretty outrageous."

Why? cancer is caused by accumulations of mutations and though oxidative stress contributes to this, most serious mutations are caused by errors in enzymatic activity - insufficient proofreading, inaccurate recombination, check points failure etc. and also by other environmental insults like cigarette smoke and ionizing radiation. At the same time immune system uses ROS to combat rogue (pre)cancer cells. It is totally conceivable that excess of antioxidants can inhibit this function more than contributing to oncogenesys.

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14. Oldnuke on January 11, 2013 4:22 PM writes...

Perhaps Klapotke will chime in with the mother of all anti-bowel cancer drugs...

Just stand back when it hits bottom.

Pauling is probably rolling in his grave reference the comments on Vitamin C!

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15. Gretchen on January 11, 2013 7:22 PM writes...

I don't have Watson's clout, but I also blogged about the dangers of excess antioxidants in 2009.

http://wildlyfluctuating.blogspot.com/2009/05/on-antioxidants.html

Rereading the post, I realize I did go on and on, and much of it is mostly of interest to people with diabetes.

But I think the problem is that too many people go overboard with the current fad supplement/food. I don't think blueberries cause cancer, but perhaps huge amounts of antioxidants as Linus Pauling took them could. Pauling did die of cancer, albeit at a rather advanced age.

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16. Lane Simonian on January 12, 2013 1:30 AM writes...

The line under James Watson's name could also read never gave proper credit to the role of Rosalind Franklin in the discovery of DNA.

Brilliant people sometimes say some not so brilliant things. Sure if your goal is to kill cancer cells than antioxidants can get in the way, but in the process you also kill healthy cells. Thus, some people die from the treatment before they die from the disease. It is one more example of taking a sledge hammer to a disease rather than targeting the causes of the disease.

All sorts of caveats can be made: under certain circumstances such as high levels or in presence of transition metals, some anti-oxidants can become pro-oxidants. Many antioxidants due to metabolism or excretion never reach the levels necessary to treat the cause of the disease. Certain forms of some vitamins may counteact the antioxidant effects of other forms of the same vitamin (such as different forms of Vitamin E). Certain antioxidants act as stimulants and can increase blood pressure and agitation. But none of this argues against the potential of antioxidants to treat many diseases.

An excellent review on the subject of oxidants (and especially nitric oxide and peroxynitrites) in disease is Pacher, Beckman, and Liaudet, Nitric Oxide and Peroxynitrites in Health and Disease. Many diseases are the result of oxidative stress and inflammation. Treat the origins of the oxidation and the inflammation and you can at least delay the onset of many diseases, Pinpoint the principal oxidant or oxidants and you can potentially treat the disease with specific antioxidants

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17. dearieme on January 12, 2013 11:15 AM writes...

"Co-discoverer of DNA": oh no he wasn't. Of its structure, certainly, but the stuff itself had been discovered earlier. Otherwise he couldn't have been involved in a race to discover its structure, could he?

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18. dearieme on January 12, 2013 11:15 AM writes...

"Co-discoverer of DNA": oh no he wasn't. Of its structure, certainly, but the stuff itself had been discovered earlier. Otherwise he couldn't have been involved in a race to discover its structure, could he?

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19. Andy on January 13, 2013 6:44 PM writes...

More the point about what Watson actually did: he proposed a model for DNA structure consistent with the existing data (including Franklin's DNA crystal diffraction data), that turned out to be largely correct upon further analysis.

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20. Healthy on January 14, 2013 9:08 AM writes...

A colleague and ex-flatmate worked for long time on the relation and ROS and exercise and the conclusion always remained the same: When you practice exercise you increase your ROS levels but also the capability to naturally anti-ROS, thus when a potential amount of ROS appears in your body if you are more prepared due to exercise you are more likely to fight it properly. Besides it has been known for a long time that high amounts of exogenous anti-ROs lead to a reduced production of natural anti-ROS which are way more powerful. Bottom line, train you anti-ROS don't spoil'em!
For funding, research and peer finding please refer to the non-profit Aging Portfolio.

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21. PSBrookes on January 16, 2013 8:39 PM writes...

With all due respect to Jim Watson, welcome to 2013! The notion that the "radicals bad/antioxidants good" theory was bunk, has been floating around since almost the day it was proposed. It's simply staggering that this is news to anyone (although I guess when JW says it then people suddenly pay attention). Suggested reading for more up-to-date research on this topic is the journal "Free Radical Biology & Medicine", which is the society journal for SFRBM (www.sfrbm.org). This type of discussion is daily bread for their journal and the society's annual meeting, for at least the past 2 decades.

(disclaimer, I'm a member and formerly on the council of SFRBM)

Also FYI, an interesting article in SciAm this week on essentially the same topic, this time with David Gems as the proponent. Gems is somewhat "closer to the fire" on this issue than Watson.
http://www.scientificamerican.com/article.cfm?id=is-free-radical-theory-of-aging-dead

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