Reactive Oxygen Species Are Your Friends!
The line under James Watson's name reads, of course, "Co-discoverer of DNA. 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. 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. . .
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