3-(5-Nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline induces ROS-mitochondrial mediated death signaling and activation of p38 MAPK in murine L1210 leukemia cells
Abstract:
Quinazoline derivatives are multitarget agents with a broad spectrum of biological activity. 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline (NTCHMTQ) is a new synthetically prepared derivative, which in our previous studies showed antiproliferative and apoptosis inducing activities towards murine L1210 leukemia cells. The aim of this study was to provide the insight into the molecular mechanism regulating NTCHMTQ-induced apoptosis in L1210 cells. The activity of caspases 3, 8 and 9, generation of reactive oxygen species (ROS), mitochondrial membrane potential changes, release of cytochrome c, degradation of PARP and activation of c-Jun N-terminal kinase 1/2 (JNK1/2), p38 MAPK and extracellular-regulated kinase 1/2 (ERK1/2) were investigated. NTCHMTQ induced production of ROS, activation of caspases 3 and 9, cytochrome c release, PARP cleavage and activation of p38 MAPK, with no activation of JNK1/2 and ERK1/2. Our resuls clearly demonstrate that NTCHMTQ induces apoptosis of L1210 leukemia cells through ROS-mitochondrial mediated death signaling and activation of p38 MAPK.