Study Finds Abundance of Iron Drives Cell Death, Offering Potential Treatments for Neuroblastoma

March 4, 2021
Aislinn Antrim, Associate Editor

Investigators are set to begin testing sulfasalazine and auronofin, which are FDA-approved to treat rheumatoid arthritis, in cancer cell models.

Although iron has been found to help cancers grow and survive, new research suggests that an abundance of iron can drive cancer cell death and potentially offer new treatment options for neuroblastoma.

According to the researchers at the Virginia Commonwealth University Massey Cancer Center, neuroblastoma is a cancer that develops in nerve tissue, most commonly in glands around the kidneys. The MYCN gene is overexpressed in 20% to 25% of neuroblastomas, and MYCN-amplified neuroblastoma contributes to a considerable amount of pediatric cancer-related deaths.

The investigators aimed to examine how MYCN and iron can drive cancer cell death in neuroblastoma and how these could potentially be targeted with novel treatments.

“Iron is a double-edged sword in a cancer cell,” explained study lead Anthony Faber, PhD, a co-leader of the Developmental Therapeutics research program at Massey, in a press release. “It can help the cancer grow and survive, but it also creates these toxic molecules within the cell called reactive oxygen species.”

Reactive oxygen species (ROS) are highly unstable molecules that react with others within a cell, causing damage to genes and resulting in a type of cell death called ferroptosis. Ferroptosis is a recently discovered type of cell death that is largely influenced by the accumulation of iron. However, there is a relatively limited scientific understanding of ferroptosis and which cancers may be prone to ferroptosis-inducing drugs.

Through previous research, Faber and his colleagues have determined that the MYCN gene creates a vulnerability to drugs that induce ferroptosis. By ramping up the systems that remove toxins on a cellular level, MYCN generates so much iron that it also initiates a weakness to drugs that block the ability of the cell to eliminate ROS, according to the press release. The investigators found that blocking these detoxifying systems with available drugs makes MYCN-amplified cells weaken and die.

“As MYCN continues to be one of the most important targets in cancer therapeutics, this study highlights a new and clinically important strategy for treating MYCN-associated cancers,” Faber explained in the press release.

Using preclinical tumor models and funding from an American Cancer Society grant, Faber’s team will test the ability of sulfasalazine and auronofin to induce ferroptosis and tumor responses in neuroblastoma cells with high levels of MYCN. Both drugs are FDA-approved to treat rheumatoid arthritis. If they show positive results testing these drugs in cancer models, Faber said the investigators can confidently begin testing these therapies in clinical trials.

“This Mission Boost Grant from the American Cancer Society allows us to conduct one of the earliest studies to link a cancer-driving gene to ferroptosis,” Faber concluded in the press release. “This is a significantly important field of study that may have far-reaching implications in cancers beyond neuroblastoma, including some small cell lung cancers and triple-negative breast cancer, which rely on a similar protein (c-MYC) to drive their growth.”

REFERENCE
Abundance of iron drives cell death and could be a key to development of novel treatments for neuroblastoma [news release]. Virginia Commonwealth University; February 19, 2021. https://www.massey.vcu.edu/about/news-center/2021-archive/abundance-of-iron-drives-cell-death-and-could-be-key-to-development-of-novel-treatments-for-neuroblastoma/. Accessed February 23, 2021.