fatostatin and betulin

Over the past few decades, mortality resulting from cardiovascular disease (CVD) steadily decreased in western countries; however, in recent years, the decline has become offset by the increase in obesity. Obesity is strongly associated with the metabolic syndrome and its atherogenic dyslipidemia resulting from insulin resistance. While lifestyle treatment would be effective, drugs targeting individual risk factors are often required. Such treatment may result in polypharmacy. Novel approaches are directed towards the treatment of several risk factors with one drug. Studies in animal models and humans suggest a central role for sterol regulatory-element binding proteins (SREBPs) in the pathophysiology of the metabolic syndrome. Four recent studies targeting the maturation or transcriptional activities of SREBPs provide proof of concept for the efficacy of SREBP inhibition in this syndrome.

Topics: Animals; Humans; Metabolic Syndrome; Protein Kinase Inhibitors; Pyridines; Sterol Regulatory Element Binding Proteins; Thiazoles; Triterpenes

The clinical success of EGFR inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Here, we show that inhibition of SREBP increase gefitinib sensitivity in vitro and in vivo. Interference of SREBP1 binding partner MARVELD1 potentiate the therapeutic effect of gefitinib as well. Mechanistically, SREBP inhibition decreases the cell membrane fluidity, results in a decreased tyrosine phosphorylation of EGFR. Therefore, targeting lipid metabolism combined with EGFR-TKIs is potentially a novel therapeutic strategies for cancer treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Gefitinib; Humans; Hydroxycholesterols; Lung Neoplasms; Membrane Proteins; Mice; Mice, Nude; Microtubule-Associated Proteins; Protein Kinase Inhibitors; Pyridines; Quinazolines; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Thiazoles; Triterpenes; Xenograft Model Antitumor Assays