Antioxidants May Promote Metastasis in Melanoma
October 23, 2015Even though the data are preliminary, findings from a new study may shed some light on why supplementing with antioxidants may be a bad idea for patients with cancer.
The results of this study, which are published online in Nature, suggest that at least in melanoma, antioxidants promote disease progression by promoting metastasis.
“Our data suggest cancer cells benefit more from antioxidants than do normal cells,” said lead author Sean Morrison, PhD, director of the Childrens Research Institute and Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center in Dallas, Texas. “It raised the concern that people with cancer may want to think twice before they supplement their diet with large doses of antioxidants.”
In their study, human melanoma cells taken from several patients were xenografted into NOD-SCID-Il2rg–/– mice. In mice that were given the antioxidant N-acetyl-cysteine, cancer spread was accelerated. It significantly increased the frequency of melanoma cells in the blood of some of the mice and significantly increased metastatic disease burden in all of them.
“At least in the mice, the antioxidants promoted the capacity of the cancer cells to spread and metastasize,” he said.
The authors found that that metastasizing melanoma cells experience very high levels of oxidative stress, which in turn leads to the death of most of these cells. Oxidative stress therefore limits distant metastasis by melanoma cells. But by administering antioxidants to the mice, more of the metastasizing melanoma cells were able to survive and increase the metastatic disease burden.
Even though this study was done in mice, Dr Morrison feels that the results can be extrapolated to humans. “We have previously shown that the behavior of human melanomas in mice are predictive of how melanoma behaves in humans,” he told Medscape Medical News. “But it is important to remember that our study was performed in mice and not in actual human patients.”
Other studies demonstrated that when cancers first initiate, they also experience oxidative stress, and that the initiation of new cancers can be promoted by antioxidants, Dr Morrison pointed out. “Our study is different in that we studied the later stages — cancer spread rather than initiation.”
“But there is also clinical evidence that in human trials, antioxidants might not be a good idea in the context of cancer,” he added. “Our paper provides a potential mechanism why cancer patients getting antioxidants may have worse outcomes.”
Detrimental Effects in Clinical Trials
As previously reported by Medscape Medical News, data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which sought to determine whether these supplements could protect against the development of prostate cancer, found that for certain men, antioxidant supplements actually increased the risk for prostate cancer.
The results of another study also cast doubt on antioxidants, this time in lung cancer. These findings showed that patients with early-stage non-small cell lung cancer did not benefit from taking selenium and also suggested harm. The rate of a second primary tumor was higher in the group that received the antioxidant, but it was not statistically significant and therefore could have been due to chance.
Another study looked at the underlying genetics to shed more light on which population of men who already have prostate cancer might be most harmed by selenium. Among men with the AA genotype, higher selenium levels were associated with a 40% reduced risk of presenting with aggressive disease (relative risk, 0.60), whereas among men with the V allele (VV or VA genotype), higher selenium levels were associated with an almost doubling of the risk for aggressive disease (relative risk, 1.82; P = .007 for the interaction).
Phillip Kantoff, MD, director of the Lank Center for Genitourinary Oncology, and vice chair and chief, Division of Solid Tumor Oncology, Department of Medical Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, was the senior author on the genetic study. He was approached by Medscape Medical News to comment on the current study.
The study is interesting, he noted. “There is a fair amount of data supporting this. In fact, there are 2 follow-up studies of SELECT study showing that over time the arms that got vitamin E or selenium had more or more aggressive cancers.”
“The underlying mechanism is still not clear but this is one possible one,” Dr Kantoff added.
The next step is increasing an understanding of the underlying mechanisms and potentially developing therapies, explained Dr Morrison.
“We know from our experience that cancer cells adapt, so that they can cope with the oxidative stress,” he said. “We want to better understand the metabolic changes that allow them to do that, with the hope that we can develop therapies that interfere with metabolic changes that increase the amount of oxidative stress.”
Increasing the amount of oxidative stress would theoretically make it more difficult for metastasis to occur. “We want to test whether increasing oxidative stress through the use of pro-oxidants would prevent metastasis,” Dr Morrison said, “But we need to better understand the metabolic changes occurring in cancer cells first.”
The authors have disclosed no relevant financial relationships.
Nature. Published online October 14, 2015. Abstract