New research shows that antioxidants — notably, vitamin E — promote metastasis in lung cancer through a variety of pathways. The implications from these basic research studies are that taking antioxidants to prevent cancer or after being diagnosed with cancer may be a bad idea.

The findings are described in a pair of related articles published online on June 27 in Cell.

In one article, senior author Michele Pagano, MD, chair of the Department of Biochemistry and Molecular Pharmacology, NYU Langone/NYU School of Medicine, New York City, and colleagues detail how genetic mutations known to promote antioxidant production increase intracellular levels of the protein Bach1, a known driver of cancer cell metastasis.

In the second article, senior author Martin Bergo, MD, PhD, Karolinska Institute, Stockholm, Sweden, and colleagues detail how increases in dietary vitamin E also increase intracellular Bach1 and promote cancer spread in a mouse model of lung cancer.

The Swedish team also shows how glycolysis increases the metabolism of glucose into the cell as well as lactic acid levels. It is the stockpiling of glucose from the bloodstream that enhances the ability of cancer cells to metastasize.

Commenting on both articles in a preview article in the same issue of Cell, Nicole Anderson, MD, and M. Celeste Simon, MD, both from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, state that the complementary findings from both teams demonstrate that stabilized Bach1 is central to metastasis in non–small cell lung cancer (NSCLC).

The clinical implications of this research are simple. "For lung cancer patients, taking vitamin E may cause the same increases in cancer's ability to spread as mutations that our team has linked to shorter survival," Pagano's coinvestigator Thales Papagiannakopoulous, PhD, NYU School of Medicine, said in a statement.

"We hope these findings help to dispel the myth that antioxidants like vitamin E help to prevent every type of cancer," he emphasized.

Inhibiting Bach1 Degradation

During tumorigenesis, cancer cells generate high levels of reactive oxygen species (ROS), the researchers explain.

Approximately 30% of NSCLC patients have specific mutations in a number of genes that promote oxidative homeostasis and that allow them to increase the transcription of antioxidant genes, either by acquiring stabilizing mutations, such as in the Nrf2 gene, or by acquiring inactivating mutations. Both types of mutations help tumor cells protect themselves from the cytotoxic effects of ROS, they add.

In a series of studies conducted to illuminate the molecular mechanisms by which accumulation of Nrf2 promotes metastasis in lung adenocarcinoma, Pagano and colleagues traced a series of mutations involved in the metastatic disease process and documented how each of these mutations promotes cell migration, metastasis, and ultimately activation of the Bach1 transcriptional program.

Activation of the metastatic program induced by the loss of some of these genes is linked to the accumulation of Bach1, the researchers note.

Expression of Bach1 genes in adenocarcinoma tissue of the lung is also associated with high-grade, advanced-stage, highly metastatic disease, as well as shortened survival, Pagano and colleagues point out.

Antioxidants and Bach1

The findings reported by Pagano and colleagues complement results reported by Bergo and colleagues, who found that supplementing the diet with either N-acetylcysteine or dietary vitamin E promotes metastasis by increasing intracellular Bach1 in mouse models of lung cancer.

The study by Bergo and colleagues showed that Bach1 stimulates glycolysis-dependent lung cancer metastasis and that it is activated under conditions of reduced oxidative stress.

In a series of experiments, Bergo and colleagues traced how antioxidants stimulate lung cancer metastasis through a series of identifiable genetic events; how the long-term administration of antioxidants increases the invasiveness of lung cancer cells and reduces ROS; and how the same antioxidants stabilize Bach1 by reducing ROS levels. All of these processes promote metastasis.

"We now have important new information on lung cancer metastasis, making it possible for us to develop new treatments, such as ones based on inhibiting Bach1," Bergo said in a statement.

In 2014, this team of Swedish researchers showed that antioxidants, such as vitamin E, taken in doses typically used in dietary supplements, accelerate tumor growth. The new research explains the mechanisms involved.

Pagano is a paid consultant for Cullgen Inc, Kymera Therapeutics, and BeyondSpring Pharmaceuticals. He has also received royalties from ThermoFisher and consulting fees from Cello Health, Japan Tobacco, Merck Research Laboratories, and Millipore. Bergo has disclosed no relevant financial relationships.

Cell. Published online June 27, 2019. Article 1, abstract; Article 2, abstract; Preview article, abstract

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