title: GS-2, a pyrazolo[1,5-a]indole derivative with inhibitory activity of topoisomerases, exerts its potent cytotoxic activity by ROS generation.
abstract: Pyrazolo[1,5-a]indole derivatives, a new type of topoisomerase (topo) inhibitor, demonstrate a broad spectrum of antitumor activities. However, the mechanism underlying the induced cytotoxicity remains unclear. In this study, we investigated whether GS-2, one of the derivatives, altered the levels of ROS in breast cancer MDA-231 cells and whether these ROS contributed to the observed antitumoral activity. Our data revealed that GS-2 caused a time- and dose-dependent elevation of intracellular ROS level in MDA-231 cells. GS-2 subsequently elicited notable inhibition on the expression of topos, DNA damage, activation of caspase-3, -9. The loss of mitochondrial membrane potential (MMP) was observed during the induction. The addition of N-acetyl cysteine (NAC, a well-known antioxidant) could effectively attenuate the GS-2-induced ROS enhancement and subsequent apoptosis. NAC attenuated the induced inhibition on expression of topos, indicating that topos might be the target of GS-2-induced ROS. The finding of the induced ROS provides new evidence for the molecular mechanisms of antitumor activity of pyrazolo[1,5-a]indole derivatives.
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Ji
authors.forename: Yong Ming
authors.initials: YM
authors.lastname: Zhu
authors.forename: Jian Wen
authors.initials: JW
authors.lastname: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D026942:DNA Topoisomerases / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000589511:4-(Z)-(p-dimethylaminophenylmethylene)-1-methyl-2-phenyl-4H-pyrazolo(1,5-a)indolium trifluoromethanesulfonate; D000970:Antineoplastic Agents; D000975:Antioxidants; D007202:Indicators and Reagents; D007211:Indoles; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D059003:Topoisomerase Inhibitors; D012313:RNA; D007770:L-Lactate Dehydrogenase; D020169:Caspases; D026942:DNA Topoisomerases; D005978:Glutathione; D000111:Acetylcysteine
keywords: Apoptosis; MDA-MB-231 cells; Pyrazolo[1,5-a]indole derivatives; ROS; Topoisomerase inhibitor