کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2583113 | 1130679 | 2013 | 11 صفحه PDF | دانلود رایگان |
• GS-2, a pyrazolo[1,5-a]indole derivative displayed potent cytotoxic activity against MDA-231 cells.
• GS-2 caused a time- and dose-dependent elevation of intracellular ROS level.
• GS-2 elicited notable inhibition on topo gene expression, DNA damage, activation of caspase-3, -9 and apoptosis.
• The pretreatment of N-acetyl cysteine could effectively attenuate the GS-2-induced cytotoxic responses.
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.
Journal: Environmental Toxicology and Pharmacology - Volume 36, Issue 3, November 2013, Pages 1186–1196