ABSTRACT
Thioredoxin system is an attractive target to overcome radioresistance in cancer therapy. The redox enzyme thioredoxin reductase (TrxR) plays a vital role in restoring cellular thiol redox balance disrupted by radiation-induced reactive oxygens species (ROS) generation and oxidative damage. In this study, a series of 1,2,5-selenadiazoles have been synthesized and identified as highly effective inhibitors of TrxR to disrupt the intracellular redox balance, and thus significantly enhanced the sensitivity of cancer cells to X-ray. Upon irradiation, 1,2,5-selenadiazoles displayed a marked synergistic inhibitory effect on radioresistant A375 melanoma cell through enhancement of ROS overproduction, and subsequent induction of ROS-promoted apoptotic pathways, which triggered then mitochondrial dysfunction and caspase activation, finally resulted in augment of radiotherapeutic efficacy. Interestingly, we also found the interaction sites between 1,2,5-selenadiazole and the model peptide of TrxR, which can be confirmed by MALDI-ToF-MS. These results clearly demonstrate TrxR as a potential target for therapy of radioresistant cancers, and selenadiazole derivatives may be attractive radiosensitizing agent by targeting TrxR.
Subject(s)
Azoles/pharmacology , Enzyme Inhibitors/pharmacology , Gamma Rays , Neoplasms/drug therapy , Neoplasms/radiotherapy , Organoselenium Compounds/pharmacology , Radiation-Sensitizing Agents/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Apoptosis/drug effects , Azoles/chemical synthesis , Azoles/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Neoplasms/enzymology , Neoplasms/pathology , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Radiation Tolerance/drug effects , Radiation-Sensitizing Agents/chemical synthesis , Radiation-Sensitizing Agents/chemistry , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/metabolism , Tumor Cells, CulturedABSTRACT
In the title compound, C(8)H(3)F(4)NO(3), the carb-oxy group lies nearly in the plane of the ring with a C-C-C-O torsion angle of -10.5â (4)°. The carbamoyl group is almost perpendic-ular to the benzene ring [C-C-C-O torsion angle = 82.2â (4) °]. In the crystal, molecules are linked via O-Hâ¯O and N-Hâ¯O hydrogen bonds involving the carbamoyl and carb-oxy groups.
ABSTRACT
Two new pentahydroxylated steroids, (3ß,12ß,16ß,23E)-cholesta-5,23-diene-3,12,16,20,25-pentaol (1) and (3ß,12ß,16ß)-cholesta-5,25(26)-diene-3,12,16,20,24-pentaol (2), were isolated from the EtOH extract of the South China Sea gorgonian Subergorgia suberosa. In addition, four known steroids were detected. The structures of these compounds were established by spectroscopic methods and comparison of their data with those of the related known compounds. In addition, the cyctotoxicities of the compounds were evaluated against selected cancer cell lines.
Subject(s)
Anthozoa/chemistry , Antineoplastic Agents/isolation & purification , Steroids/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , China , Ethanol/chemistry , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Oceans and Seas , Steroids/chemistry , Steroids/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
OBJECTIVE: To study the secondary metabolites from the marine sponge Phakellia fusca epiphytic fungi. METHODS: The compounds were isolated by column chromatography over silica gel and purified by Sephadex LH-20 column chromatography and preparative TLC. The structures were elucidated by means of physiochemical properties and spectroscopic analyses. RESULTS: Four compounds were separated and identified as: cyclo-(L-Val-L-Pro) (1), cyclo-(L-Phe-L-Pro) (2), cyclo-(L-Tyr-L-Pro) (3), cyclo-(3-hydroxy-4-methyldecanoyl-Gly-L-Val-D-Leu-L-Ala-L-Phe) (4). CONCLUSION: Compounds 1-4 are obtained from the marine sponge Phakellia fusca epiphytic fungi for the first time.
