ABSTRACT
BACKGROUND: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and the development of drug resistance after a first platinum-based regimen. The presence of a specific population of "cancer stem cells" could be responsible of the relapse of the tumor and the development of resistance to therapy. For this reason, it would be important to specifically target this subpopulation of tumor cells in order to increase the response to therapy. METHOD: We screened a chemical compound library assembled during the COST CM1106 action to search for compound classes active in targeting ovarian stem cells. We here report the results of the high-throughput screening assay in two ovarian cancer stem cells and the differentiated cells derived from them. RESULTS AND CONCLUSION: Interestingly, there were compounds active only on stem cells, only on differentiated cells, and compounds active on both cell populations. Even if these data need to be validated in ad hoc dose response cytotoxic experiments, the ongoing analysis of the compound structures will open up to mechanistic drug studies to select compounds able to improve the prognosis of ovarian cancer patients.
Subject(s)
Antineoplastic Agents/pharmacology , High-Throughput Screening Assays , Neoplastic Stem Cells/drug effects , Ovarian Neoplasms/drug therapy , Small Molecule Libraries/pharmacology , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Ovarian Neoplasms/pathology , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Trioxsalen (TRX) is a 4,5',8-trimethylated psoralen analog presenting interesting biological activities when irradiated with UVA light. A series of TRX derivatives, which where obtained by its chemical modification and incorporation of a variety of unsaturated functions at position 4' of the psoralen ring-system, were evaluated for their antioxidant activity and their inhibitory activity on soybean lipoxygenase (LOX) and lipid peroxidation. The reducing properties of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay and found to be very low, in the range 0-14%, with the exception of the hydroxamic acid 6 which showed almost identical activity to BHT. TRX derivative 3 significantly inhibited LOX, with IC(50) 9.4 muM. With the exception of TRX, all tested analogs inhibited lipid peroxidation in the range of 35-91%. The most potent compound, namely TRX derivative 3, was studied for its anti-inflammatory activity in vivo on rat paw edema induced by carrageenan, and was found to be of almost identical activity to indomethacin. The results of the biological tests are discussed in terms of structural characteristics.
Subject(s)
Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase/metabolism , Trioxsalen/analogs & derivatives , Trioxsalen/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Biphenyl Compounds/metabolism , Carrageenan/chemistry , Edema/chemically induced , Edema/drug therapy , Female , Free Radical Scavengers/metabolism , Hindlimb , Indomethacin/pharmacology , Indomethacin/therapeutic use , Inflammation/chemically induced , Inflammation/drug therapy , Inhibitory Concentration 50 , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Lipoxygenase Inhibitors/therapeutic use , Male , Picrates/metabolism , Rats , Glycine max/enzymology , Trioxsalen/chemistry , Trioxsalen/therapeutic useABSTRACT
NMR studies have been used to examine conformational effects in thyrotropin-releasing hormone (TRH), the epimer incorporating D-His, and their analogues where trans- and cis-4-hydroxy-L-proline replace L-proline (Pro). In all six compounds the observed overall conformation of the major conformer around the Pro-His amide bond, and the observed increase of the cis/trans ratio between the conformers when L-His is replaced by D-His, can be accommodated by assuming that a ten-membered ring is formed by hydrogen bonding between the N-H of the Pro carboxamide function and the N pi-atom of the His imidazole nucleus.
Subject(s)
Thyrotropin-Releasing Hormone/chemistry , Amino Acid Sequence , Histidine , Hydroxyproline , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Protein ConformationABSTRACT
A 65-year-old woman with an acute myocardial infarction, as judged by serial enzyme changes, developed transitory Q waves in leads V2 to V4 and leads 2, 3, and aVF during an attack of pain in the chest. These Q waves were not present 12 hours later. It is suggested that these changes represent a focal block in the septal fibers of the left bundle-branch system. This defect could underlie the transient right precordial Q waves seen in myocardial infarction or ischemia, as well as the fixed Q waves of many patients without septal infarction at autopsy.
Subject(s)
Bundle of His/physiopathology , Bundle-Branch Block/etiology , Heart Conduction System/physiopathology , Myocardial Infarction/complications , Aged , Angina Pectoris , Bundle-Branch Block/diagnosis , Bundle-Branch Block/physiopathology , Electrocardiography , Female , Humans , Myocardial Infarction/physiopathology , Time FactorsABSTRACT
A 23-year-old man had Prinzmetal's variant angina. After strenuous exercise and isoprenaline infusion the electrocardiogram remained normal and the patient asymptomatic. Coronary angiography gave normal results which remained normal after administration of ergometrine. An injection of methacholine induced an attack.
