December 2020

ONCOLOGY

MITOCHONDRIA-TARGETED ANTIOXIDANTS INHIBIT TUMOR GROWTH

Featuring: Navdeep Chandel, PhD
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​​Northwestern Medicine investigators have discovered that inserting dietary antioxidants into the mitochondria of cancer cells may inhibit overall tumor growth, according to a study published in Science Advances.
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Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, was the senior author of the study.

Antioxidants effectively scavenge and discard oxidants, or reactive oxygen species (ROS), produced by the mitochondria. A buildup of mitochondrial ROS can activate cell signaling pathways that support cancer cell survival and proliferation. Previous work, however, has found that dietary antioxidants, either found naturally in food or ingested through oral supplements, can actually accelerate tumor growth for this very reason.

Considering this contradictory evidence, the investigators aimed to determine if inserting dietary antioxidants directly into the mitochondria of cancer cells could prevent the generation of mitochondrial ROS to reverse this effect and inhibit overall tumor growth.

Using CRISPR-based genetic screening to study mouse models of T-cell acute lymphoblastic leukemia, the investigators found that mitochondrial complex III — one of five major complexes in the mitochondria’s electron transport chain which produces energy for the cell — is a major source of hydrogen peroxide (H202) production, which is associated with cancer cell proliferation.

The team hypothesized that inhibiting hydrogen peroxide production could be accomplished by inserting a dietary antioxidant into the mitochondria of these cancer cells and reducing the overall amount of cancer present.

Mitochondria produce local pools of hydrogen peroxide to promote pro-tumorigenic pathways, but too much of it can damage and kill cancer cells. In this case, the antioxidant vitamin E localized to mitochondria inhibited the production of this mitochondrial hydrogen peroxide, preventing the activation of pro-tumorigenic pathways and, ultimately, cancer cell proliferation.

As for clinical applications, drugs that scavenge hydrogen peroxide from mitochondrial complex III may be effective in decreasing tumor growth for different types of cancer, according to Chandel.

“This is less about prevention, but more could you manipulate mitochondrial H202 production to prevent tumor growth,” said Chandel, who is also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

As for next steps, Chandel said his team plans to use CRISPR based genetic screening to determine whether manipulating other dietary antioxidants can inhibit tumor growth and reduce overall tumor burden without altering normal cells.

Hyewon Kong, a fifth-year student in the Driskill Graduate Program in Life Sciences, was the first author of the study.

The current study was done in collaboration with the laboratory of David Sabatini, PhD, at the Whitehead Institute for Biomedical Research in Cambridge, Mass. This work was supported by National Institutes of Health grants 5R35CA197532 and 2T32HL076139-16, a National Cancer Institute grant T32 CA009560 and a Cancer Research Institute Irvington postdoctoral fellowship.

This article was originally published in the Feinberg School of Medicine News Center on December 7, 2020.
Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, and a professor of Biochemistry and Molecular Genetics, was the senior author of the study published in Science Advances.

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