piperidines and carvacrol

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 μM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.

Topics: Adenosine Triphosphate; Brain Neoplasms; Caspase 3; Caspase 7; Cell Death; Cell Line, Tumor; Cymenes; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Monoterpenes; Piperidines; Protein Serine-Threonine Kinases; Quinolines; TRPM Cation Channels

We screened natural organic compounds, which affected the lipid accumulation and the lipid body formation in oleaginous yeast, Lipomyces starkeyi, generating large lipid bodies. We found that four natural components in spices, carvacrol, thymol, eugenol, and piperine, inhibited the lipid accumulation at concentrations of 20-50 mg/L with a slight growth inhibition. The inhibitory effects were quantitatively represented by the total lipid accumulation amount, the triacylglycerol accumulation amount, and the average lipid body size. At 50 mg/L, the effects of these compounds were not identical and exhibited 11-37% decrease in lipid amount and 15-21% decrease in lipid body size with 13-39% decrease in cell growth. The inhibitory effect of these compounds lead to 30-69% decrease in triacylglycerol accumulation without any additional accumulation of its intermediates, suggesting that they will suppress the total carbon inflow into the triacylglycerol biosynthesis.

Topics: Alkaloids; Benzodioxoles; Cymenes; Eugenol; Hypolipidemic Agents; Lipid Metabolism; Lipids; Lipomyces; Monoterpenes; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Spices; Thymol; Triglycerides