The cotton plant could help treat incurable brain cancer

Glioblastoma is the most common and lethal of malignant brain tumors. Standard treatment includes the three current therapeutic axes: surgical resection, radiotherapy and temozolomide chemotherapy.

However, despite the potency of the treatment, median survival does not exceed 15 months and barely 10% of patients survive beyond 5 years from their diagnosis.

The effectiveness of treatments is limited due to the ability of tumor cells to invade and infiltrate the healthy tissue around them, along with their resistance to radio-chemotherapy. In this sense, current therapeutic management of glioblastoma is merely an ephemeral barrier to the inevitable tumor relapse.

These limitations have prompted the search for new therapeutic approaches, mainly based on the identification of drugs that are more effective in the eradication of tumor cells.

Resistance to cell death is one of the hallmarks of tumor cells and one of the main reasons for recurrence. In fact, the main cause of chemotherapy failure is the failed activation of cell death.

Cell death can occur from the activation of different intracellular pathways. A cell that fails to function properly must be inexorably eliminated to ensure the proper functioning of the tissue or organ of which it is part. It is therefore not surprising that there are different intracellular alternatives for this purpose. The environment and the internal context of the cell play a central role in the activation of a certain mechanism or subroutine of cell death.

The ultimate goal of antitumor treatment is to eliminate the malignant cell, independently of the activated cell death subroutine. However, basic knowledge has shown us that activated intracellular pathways will be decisive, not for the elimination of the cell per se, but in the intercellular communication between the dying cell and its neighbors. This dialogue can be critical in the progression of the tumor itself.

In this regard, and by way of example, a pro-inflammatory extracellular context is frequently associated with increased aggressiveness of glioblastoma. The only subroutine of cell death that does not cause inflammation is apoptosis.

On the contrary, necrotic cell death or necrosis generates a highly inflammatory environment. Glioblastoma cells are characterized by a process of cell death closer to necrosis than to apoptosis when exposed to different pro-apoptotic challenges.

Difficulties in eliminating glioblastoma tumor cells

Apoptosis is characterized by the activation of a series of proteins called caspases. They fragment other proteins within cells, dismantling in an orderly way the cellular machinery essential for life.

One of the key points during apoptosis is the breakdown of DNA and the cell nucleus, which marks the point of no return of cell death. To this end, caspases activate a protein that cleaves DNA (an endonuclease), known as DFF40/CAD.

This protein is ultimately responsible for two biological processes that differentiate apoptosis from other cell deaths: a type of specific degradation of DNA and the fragmentation of the cell nucleus.

In its inactive form, it is localized in the cell cytoplasm. This location is crucial for it to be activated by caspases, after which it is directed to the nucleus to fragment the DNA.

Glioblastoma has two irregularities that make it difficult for caspases to activate the aforementioned protein: first, low levels of expression of this endonuclease relative to other tumors; and second, an unusual location of this protein in the cell nucleus.

Both characteristics add up preventing the dismantling of the cell nucleus and its components. This scenario makes it difficult for the dying tumor cell to exceed the threshold of the point of no return that apoptosis would provide.

Drugs that fragment the nucleus of tumor cells: gossypol

Encouraged by the fact that these tumor cells continue to express DFF40/CAD, we began the search for drugs capable of activating this protein and promoting cell nucleus fragmentation.

Among the drugs tested, gossypol gave us the best results. Gossypol is a compound that is extracted from the cotton plant, of the genus Gossypium. It was first isolated in the late 19th century as a highly photosensitive yellow pigment.

It is also a by-product detected in the oil extracted from the seed of the cotton plant, for food use. Its consumption was associated with a decrease in male fertility, arousing the interest of the scientific community.

Despite its potential as a male contraceptive, gossypol has never reached the market as such. Currently, it is an experimental drug widely studied for its antitumor properties. Our laboratory has shown that at high concentrations, gossypol promotes nuclear fragmentation of glioblastoma cells, forcing them to cross the point of no return in cell death.

Gossypol is the first link in the discovery of new drugs useful in the therapy of glioblastoma. We now know that the limitations of this type of tumor in activating apoptosis beyond the point of no return can be overcome by using the appropriate drug.

Thus, a new line of research is opened to develop new treatments and more effective strategies for this type of cancer, which is currently incurable.

We hope that in the coming years new drugs with a function similar to gossypol will appear that will allow us to face the therapeutic challenges posed by glioblastoma and, let's trust, other aggressive tumors.

Article originally published in The Conversation - By Judit Ribas Fortuny, Associate Professor of Pharmacology, University of Lleida; Jordi Bruna Escuer, Coordinator of the Neuro-Oncology Unit, Bellvitge-ICO University Hospital L'Hoapitalet, Bellvitge Biomedical Research Institute (IDIBELL); and Victor José Yuste Mateos, Full Professor at the University of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona.

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