?Neuroblastoma, one of the most common, aggressive forms of cancer in many young children, exhibits an increased resistance to the current generation of chemotherapy. To be able to treat these sorts of tumors, a new type of therapy is required. Research from VIB, Ghent University, and the University of Antwerp, led by the brothers Tom and Wim Vanden Berghe, has led to the discovery of a new molecular mechanism that can kill cancer cells in mice. Withaferin A, an active substance from a medicinal plant extract (Ashwagandha) from traditional medicine in India, plays an important role in this. These insights were published in the prestigious scientific journal Journal of Clinical Investigation.

Dr. Tom Vanden Berghe (VIB-Ghent University): “The clarification of the working mechanism of Withaferin opens perspectives for new strategies to treat these aggressive tumors. These first results in mice are very promising and have come to light thanks to the support of Stichting tegen Kanker [Foundation against Cancer], but there is still a long way to go before we can use this as real treatment in practice.”

Difficult-to-handle cancer in children

Neuroblastoma typically occurs in young children; over half of patients are under 2 years old. This aggressive form of cancer is coupled with an elevated resistance to chemotherapy. This sort of resistance often emerges through defects in the molecular mechanisms that in normal circumstances lead to the destruction of cancer cells (cell death). The challenge is to find alternative molecular pathways to kill the cancer cells. VIB-Ghent University researchers in Dr. Tom Vanden Berghe and Professor Peter Vandenabeele's team, in collaboration with Professor Wim Vanden Berghe of the University of Antwerp, have discovered how Withaferin A kills aggressive neuroblastoma cancer cells.

Professor Wim Vanden Berghe says: "The roots and leaves of the Withania somnifera, commonly known as Indian ginseng or Ashwagandha, have been used for thousands of years in traditional medicine in India (Ayurvedi) to treat ulcers and cancer. Extracts from plants, but also from fungi and marine organisms, are important sources to identify chemical structures that can be used as medicines. Traditional medicine is often based on centuries-old practices that can potentially lead to new types of medicines."

Ferroptosis: A newly discovered type of cell death

Researchers with years of experience in cell death have been able to demonstrate that Withaferin A triggers a sort of biological rusting in mice called ferroptosis. The term ferroptosis refers to an iron-driven oxidation reaction of the membranes of cancer cells, which quickly kills off the cells.

As part of his doctoral research, Behrouz Hassannia was successful in showing the superior efficacy of Withaferin A in comparison to current chemotherapies in mice, after administering locally. In most mice, no relapse was observed. Behrouz Hassannia said, “We successfully administered Withaferin A intravenously by locking it inside nanoparticles. These accumulate in the tumor, leading to efficient killing of the tumor cells and reduced side effects. This offers important prospects for an improved neuroblastoma treatment, but also for other chemo-resistant cancers.”

Tom Vanden Berghe says, “These crucial new insights into how we can initiate ferroptosis (or biological rusting) in chemotherapy-resistant tumors was only possible thanks to the collective efforts of an international team of researchers with extremely diverse expertise, ranging from neuroblastoma cancer, nanotechnology, pharmacology, molecular biology, and epigenetics to advanced technologies like oxidative lipidomics.”