Cell death is a key part of life

Every day, an average human adult loses billions of cells as our bodies self-regulate. When cells are injured, or their genetic material too damaged, they are programmed to self-destruct, in a mechanism called apoptosis. If damaged cells keep multiplying instead, they can cause various illnesses, including cancer. One of the key questions in cancer research is finding a way to activate alternative cell death pathways in cancer cells that have developed a resistance to apoptosis. Controlled necrosis is now investigated as such an alternative death pathway and novel compounds able to trigger this type of demise are needed.

Plant fungi against cancer

Stemphol (STP) is a molecule produced by plant fungi like Stemphylium globuliferum, which causes leaf spots on alfalfa. It is known to have antimicrobial properties against some types of fungi, yeast, and bacteria — and in Pleospora herbarum, a fungi that causes disease in a variety of plants, it acts as a self-inhibitor, slowing the growth of the fungus that produces it. Prof. Marc Diederich and his colleagues have tested stemphol’s effect on cancer cell death – finding amazing results. STP has a limited effect on healthy cells but is devastating on cancerous ones by activating a specific form of necrosis.

Stemphol triggers the death of cancerous cell by hijacking the mechanisms that regulate their delicate calcium balance. Binding to one of their receptors, it tells the calcium storage units of the cell to release all of their reserves inside the cytosol – the liquid inside the cell. This alone causes apoptosis, but the consequences do not stop there. Mitochondria, which produce energy and regulate the metabolism of the cell, also get overloaded with calcium and damaged – causing necrosis. With those two mechanisms at play, the cancer cell is destroyed.

Not only does stemphol trigger cell death, it also makes them release a chemical signal – a “damage associated molecular pattern” (DAMP) — that calls a response from the immune system. The particular DAMP in this case – HMGB1 – has never before been observed as a result of chemotherapeutic compound treatment for patients with acute myeloid leukaemia. This makes stemphol a promising treatment, as the release of DAMPs by AML cancer cells helps patients create a better anticancer immunity and improves their chances of surviving. The team will carry on research about stemphol, to further develop its anti-tumor potential.