An active substance that has been known for 30 years could unexpectedly turn into a ray of hope against eye tumors. This is shown by a study conducted by researchers from the Universities of Bonn and Magdeburg together with US colleagues. The plant leaves of which contain the tested substance is anything but rare: at Christmas time you can find it in every well-assorted garden center. The coralberry (Ardisia crenata) decorates many German living rooms during the winter months. At this time it forms bright red fruits, which make it a popular ornamental plant. The plant, originally from Korea, is surprisingly resistant to insect attack. Its leaves contain bacteria that produce a natural insecticide – a toxin named FR900359, abbreviated FR toxin, that was isolated for the first time 30 years ago by Japanese researchers. Another 25 years would pass before its biological mode of action was described – by none other than the research groups led by Professors Gabriele M. König and Evi Kostenis at the Institute of Pharmaceutical Biology of the University of Bonn.
This work now forms the basis for a research group of the German Research Foundation (DFG) on the group of G proteins and the possibility of their pharmacological manipulation. This toxin could soon become a star in a completely different field: as a potential drug against uveal melanoma, the most common and aggressive variant of eye cancer. FR has been the focus of pharmaceutical research for some time now: it inhibits an important group of molecules in the cells, the Gq proteins. Gq proteins have a similar function in the cell as a city’s emergency control center: when the control center receives a call, it informs the police, ambulance and fire brigade as required. Gq proteins, on the other hand, can be activated by certain control signals. In their activated form, they switch different metabolic pathways on or off. However, the cell should not permanently change its behavior. The Gq proteins therefore inactivate themselves after a short time. In uveal melanoma, however, a point mutation (Q209L) prevents two important Gq proteins from returning to their inactive state.
They thus remain permanently active and due to this malfunction, cells harboring this mutation begin to divide uncontrollably.Long-standing Gq signal, indeed, has in this case an unwanted side effect: it stimulates cell proliferation by activating <strong>cellular signaling</strong> cascades known as MAP-kinases. FR toxin can stop this division activity, something researchers would not have expected. Whereas Q209L accounts for approximately half of Gq mutations in eye melanoma, Q209P is as frequent as Q209L and also promotes<strong> oncogenesis</strong>, but it has an altered binding to effectors G-beta-gamma and RGS proteins. It has been known for some time that FR can prevent the activation of Gq proteins. The substance “clings” to the proteins and ensures that they remain in their inactive form. Therefore, it seemed impossible for the substance to be effective in mutated and thus permanently active Gq proteins Common understanding was that FR ignores any Gq proteins that have already been activated.
Dr. Evelyn Gaffal working at the University of Magdeburg, first author of the research, explained: “We used FR in our experiments and were surprised to find that it suppresses the proliferation of cancer cells. And now also know why this is so: the mutated Gq proteins also seem to occasionally revert into their inactive form. As soon as this happens, FR900359 intervenes and gets a firm grip on the molecule. As a result, over time, more and more Gq proteins are successively withdrawn from their activated state for good”. FR toxin has already proven its effectiveness in cell cultures and in experiments with mice suffering from cancer. But there are still a few hurdles to overcome before application in humans becomes feasible. Above all, the substance must reach the tumor cells precisely, without hitting other tissues. Gq proteins assume vital functions practically everywhere in the body. If FR would kill only the tumor cells, the drug must get right where needed. Nothing new, this is a challenge that many other chemotherapies also have to deal with.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Maziarz M et al. J Biol Chem. 2018 Dec 21; 293(51):19586-19599.
Perez DE et al. Pigment Cell Melanoma Res. 2018; 31(5):604-613.
Staby KM, Gravdal K et al. Acta Ophthalmol. 2018 Jul; 96(1):31-38.
Scholz SL et al. Invest Ophthalmol Vis Sci. 2017; 58(9):3464-3470.
Dott. Gianfrancesco Cormaci
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