Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. Under hypoxic conditions or when free fatty acids overload can occur (exogenously from the serum or due to intracellular alterations e.g. when beta-oxidation is blocked) the number of LDs are increasing. It was shown that LD accumulation occurs in vivo at prenecrotic cancer tissues and border zones of experimental myocardial infarcts, therefore LDs can be in vivo markers of cancer and ischemic insults.

Altering the amount, distribution of LDs and the rate of their formation by small molecules, membrane transport and lipid homeostasis could be impaired in cancer cells that are much more depending on fatty acid removal than normal cells, where beta-oxidation is not affected by oxygen depletion. Imbalance in lipid homeostasis can finally lead to membrane disruption of the ER membrane, from where calcium ions will be released resulting in apoptosis through the mytochondria (Borradaile NM et al.: Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 2006;47:2726).

We are now developing lipid droplet and endoplasmic reticulum binding anticancer drug candidates (for treatment of hepatic carcinoma and liver metastatic cancers) in the frame of Avinomid grant. As human gliomas contain high number of lipid droplets and they are sensitive to oxidative stress, trifluoro-phthalimides and new derivatives could be also tested for intracerebral administration against glioma.

During the project we intend to develop lipid-based drugs for glioma. Lipid-based anti-cancer drugs are neither in the process of development nor in the market at present, mostly because of pharmacokinetic problems. It will be the purpose of this project to exploit arachidonic acid (AA, 20:4 ω-6) and γ-linolenic acid (GLA, 18:3 ω-6) among others as anti-cancer drugs based on the results of previous studies.

This compound family interfere lipid vesicle formation and trafficking, a novel way to combat cancer with cytotoxicity in the range of 1-20 μM against various types of cancer cell lines.