Our Care Oncology physicians often get asked their opinion on various supplement including common and uncommon antioxidants: vitamin C, vitamin E, beta-carotene, N-acetylcysteine (NAC), and glutathione to name a few. Understandably, newly-diagnosed cancer patients and their friends and family often embark on a deep search for anything that can be done to support health and immune system function. And why not antioxidants? A steady stream of media and supplement manufactures have told us for decades that antioxidants offer a panacea of health benefits. And rightfully so, a light internet search can easily lead to articles touting the virtues of antioxidants. The calculus: They may help fight my cancer, and, in the very least, they can’t hurt. Right?
Where did the idea antioxidants are good come from?
In 1972 Denham Harman, a luminary in the field of free radical biology, proposed the mitochondrial theory of ageing. It goes like this: Inside every cell mitochondria are the center of oxidative metabolism and hence the primary source of free radical generation within the body. Free radicals generated from mitochondria then precipitate a cascade of damage to surrounding mitochondria, lipids, carbohydrates and even nuclear DNA. The cell can repair most of this damage, but over time the cell slowly loses the ability to keep up with the free radical induced damage and the net damage that ensues is the proximal cause of ageing.
A simple and intuitively seductive assumption sprang forth from Harman’s theory: free-radical quenching antioxidants should slow ageing and prevent disease. This seemingly innocent prediction has confounded a generation of molecular biologists. In the over forty years that followed Harmon’s prediction researchers have shoved antioxidants into cell cultures, mice, rats, monkeys and humans trying to prove they slow ageing and prevent disease.
Despite their best efforts to prove otherwise, an overwhelming consensus has emerged from the decades of research on antioxidants and ageing: they just don’t work. They might correct dietary deficiencies and/or perhaps confer a slight protective effect against certain diseases, but they do nothing to prolong lifespan—worse, there is evidence to suggest they may even promote certain diseases. Yet, almost a half century of inertia and a billion-dollar supplement industry that grew out of Harmon’s prediction have managed to continue propping up the notion that antioxidants are a well-spring of health. (Don’t confuse foods containing antioxidants and antioxidant supplements. Most quality food contain high amounts of natural antioxidants and a good diet has been shown to be very beneficial.)
Studies began to challenge many assumptions about antioxidants
The blanket assumption that antioxidants slow ageing and prevent disease was first seriously challenged from a large study in 1994 that followed smokers taking massive doses of the antioxidant beta-carotene. The stunning result: The smokers taking beta-carotene had an 18% increased risk of developing lung cancer. As researchers were still scratched their heads about the confusing result a trial two years later was stopped early after it was discovered that high-dose beta carotene and retinol was shown to increase the risk of developing lung cancer by 28 percent in smokers and workers exposed to asbestos. And these early studies are not proving to be flukes: a 2011 trial involving more than 35,500 men over 50 found that large doses of vitamin E increased the risk of prostate cancer by 17 percent.
Antioxidants and cancer therapy
The above studies highlight a trend of studies suggesting that antioxidants may contribute to the incidence of certain cancers under specific conditions and may make cancer more aggressive when it occurs. However, the series of studies sparked a more immediate concern to practicing oncologists: because traditional standard of care therapies like radiation and chemotherapy kill cancer cells by the generation of free radicals perhaps patients taking antioxidants were negating or diminishing the effects of their cancer treatment. Yet, despite a flurry of studies in the early 2000’s―both observation and randomized controlled trials―no clear consensus of the effect of antioxidant on standard therapies emerged. The studies reached a wide variety of conclusions, some showing improved survival and status and others, a reduction in survival. Most likely, the common antioxidants, given at normal doses, are simply to weak to overcome the powerful effects of radiation and chemotherapy.
The smoldering debate about antioxidants and cancer was rekindled again in 2012 when Nobel Prize winner and former head of the NCI, James Watson, sounded off on the danger of antioxidants in cancer, penning a review titled Oxidants, antioxidants and the current incurability of metastatic cancers, claiming the work was “His most important work since the double helix.” His epiphany, in part, was the claim that antioxidants may be thwarting most cancer therapies if not outright causing cancer by preventing the mitochondrial driven apoptotic cascade triggered by free radicals. “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. 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.” Watson goes on, “Free-radical-destroying antioxidative nutritional supplements may have caused more cancers than they have prevented.”
A series of studies in the years following Watson’s revelation seemed to support his claim. A 2015 study published in Science Translational Medicine, looked at melanoma because rates have been increasing and because the cancer is known to be sensitive to the effects of free radicals. They fed the antioxidant N-acetylcysteine (NAC) to mice that had been bred to be susceptible to melanoma at a dose consistent with what people typically consume in supplements. Although the treated mice did not develop more skin tumors than the control mice, they developed twice as many tumors in their lymph nodes, a hallmark of the spread of cancer. When the researchers added NAC or a form of vitamin E to cultured human melanoma cells, they again showed that the antioxidants improved the cells’ ability to migrate and invade a nearby membrane.
Additional evidence surfaced pointing to the danger of antioxidants new classes of free radical generating therapies. A study that came out immediately before Watson’s paper convincingly showed the importance of free radical induced apoptosis by the finding that the ‘first-in-class’ anti-cancer mitochondrial drug elesclomol kills cancer cells through promoting ROS generation. When these resulting free radicals were neutralized through the simultaneous administration of the antioxidant N-acetylcysteine, preferential killing of cancer cells stops. The failure of elesclomol to generate apoptosis in non-cancerous cells probably arises from the inherently lower ROS level generated by normal mitochondrial electron transport machinery.
Critically, many new therapies are being developed that lower the glutathione level in cancer cells rendering them more vulnerable—it is not clear how antioxidants will affect this new class of drugs and therapies.
The picture remains murky
Although there is no overwhelming consensus that antioxidants taken during cancer treatment will lead to worse outcomes the existing evidence throws up enough red flags to warrant caution. Not much is known about the effects of antioxidants in relation to many of the new metabolic-acting and immunotherapies. It must be considered that adjunctive therapies like the ketogenic diet, hyperbaric oxygen and the Care Oncology Protocol are also proposed to work by triggering oxidative stress in cancer cells while simultaneously reducing the cancer cells ability to manufacture internal antioxidants. It is not unreasonable to question the use of antioxidants concurrent with these therapies―especially considering they tend to generate much milder oxidative stress than tradition cancer therapies and therefore antioxidants might have the capacity to influence outcomes to a greater degree. In fact, evidence exists highlighting this tenuous relationship. It has been shown that some of the medications in the Care Oncology Protocol act by inducing oxidative stress within cancer cells. Both doxycycline and metformin are proposed to work by inducing an intolerable surge of free radicals within already oxidative-stressed cancer stem cells while simultaneously inhibiting a transcription factor called STAT3 that the cancer cell upregulates in order to manufacture internal, adaptive antioxidants—a sort of one-two punch. A 2017 study showed that the addition of the potent antioxidant N-acetylcysteine was able to cancel-out the therapeutic effect of doxycycline in a glioblastoma mouse model.
“What we’re starting to learn is that there can be bad cells from cancer that appear to benefit more from antioxidants than normal cells,” said researcher Sean Morrison from the University of Texas Southwestern Medical Center, who’s lab studies the effects of antioxidants on cancer cells. “Personally, from the results we’ve seen, I would avoid supplementing my diet with large amounts of antioxidants if I had cancer.”
Martin Bergö, Ph.D., of the University of Gothenburg in Sweden, said he was extremely concerned with the aggressive marketing of antioxidants to cancer patients. The data strongly suggest that using antioxidants “could be really dangerous in lung cancer and melanoma, and possibly other cancers,” he said. “And because there’s no strong evidence that antioxidants are beneficial, cancer patients should be encouraged to avoid supplements after they have a diagnosis.”
Care Oncology Science Advisor, Thomas Seyfried of Boston College shares Morrison’s and Bergö’s sediment. “Why would you give antioxidants to cancer patients? It runs completely counter to metabolic therapeutic interventions.”
Indeed, the general idea that oxidative stress might be one of cancer’s greatest vulnerabilities, and that antioxidants, both exogenous (taken orally or by IV) and endogenous (manufactured intracellularly), may represent a thin veil of protection that can be therapeutically targeted is also proving to hold true with the emerging class of immunotherapies. New research has shown that by reducing intracellular glutathione, the cell’s “master antioxidant”, the cell-killing effect of immunotherapies can be enhanced. The authors of the recent study state: “The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells.”
Well what now?
In the over forty years since Harman’s proposed free-radical driven mitochondrial theory of ageing we’ve learned that free radical biology is certainly more complex than originally appreciated. While there is no question free radicals are destructive to the cell, emerging evidence suggests mitochondrial derived free radicals may also be an important signaling system, instructing the DNA within the mitochondria to manufacture mitochondrial proteins. Free radical biology and its ultimate role in ageing is still unsettled science that has yet to be conclusively decided.
However, the relationship of antioxidants and cancer, although still murky, seems to be tilting toward a note of caution when it comes to including antioxidants as part of cancer therapy. While little if any benefit has ever been proven, the evidence pointing against their use does demand attention. A cautious approach would be to avoid high doses of antioxidants during cancer treatment. A very cautious approach would be to avoid antioxidant supplements altogether. Indeed, most dieticians agree that enough micronutrients can be obtained―and in the right ratios―from a good diet.
Some common antioxidants:
Vitamin E, selenium, zinc, N-acetylcysteine, glutathione, Vitamin C (low dose only—high doses administered by IV are oxidative), and beta-carotene
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