The effect of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline on cell growth, cell cycle, induction of DNA fragmentation, and activity of caspase 3 in murine leukemia L1210 cells and fibroblast NIH-3T3 cells

• Published in: Cell biochemistry and function Vol. 24; no. 6; pp. 519 - 530
• Main Authors: Jantova, S, Letasiova, S, Repicky, A, Ovadekova, R, Lakatos, B
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2006
• Subjects: Animals; apoptosis; Apoptosis - drug effects; caspase 3; Caspase 3 - metabolism; cell cycle; Cell Cycle - drug effects; cell growth; cell growth, cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; DNA Fragmentation - drug effects; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Fibroblasts - drug effects; Fibroblasts - metabolism; L1210 and NIH-3T3 cells; Mice; Molecular Structure; NIH 3T3 Cells; quinazoline derivative; Quinazolines - chemistry; Quinazolines - pharmacology; Time Factors; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0263-6484; 1099-0844
• DOI: 10.1002/cbf.1296

Quinazolines are multitarget agents, which have broad spectrum of biological activity, and some of them are now in cancer clinical testing. 3‐(5‐nitro‐2‐thienyl)‐9‐chloro‐5‐morpholin‐4‐yl[1,2,4]triazolo[4,3‐c]quinazoline is a new synthetically prepared derivative, which in our previous study showed cytotoxic effects on cancer cell lines HeLa and B16. Quinazoline, at micromolar concentrations, induced morphological changes and necrosis of B16 cells, and at nanomolar concentrations it produced changes of F‐actin cytoskeleton. It did not cause changes in the cell cycle, did not induce apoptotic cell death in B16 cells, did not have a mutagenic effect, and did not even behave as a typical intercalating agent. Little significant reduction of tumor volume in intramuscular transplanted B16 cells was observed. The aim of the present study was to examine the cytotoxic effect of 3‐(5‐nitro‐2‐thienyl)‐9‐chloro‐5‐morpholin‐4‐yl[1,2,4]triazolo[4,3‐c]quinazoline on murine leukemia L1210 cells and fibroblast NIH‐3T3 cells. Induction of cell morphology and cell cycle changes, induction of apoptosis and caspase 3 activity were studied. Quinazoline acted cytotoxically on both cell lines. The sensitivity of leukemia L1210 cells to the quinazoline was higher than that of fibroblast NIH‐3T3. The IC100 was 12 µM for L1210 cells and 24 µM for NIH‐3T3 cells. No effect of quinazoline on the cell cycle profile of L1210 and NIH‐3T3 was detected, however, quinazoline induced an increase of the sub‐G0 cell fraction, apoptotic DNA fragmentation, and apoptotic morphological changes at a concentration of 12 µM. This quinazoline concentration induced caspase 3 activity. Our results demonstrated that induction of apoptotic cell death via activation of caspase 3 contributed to the cytotoxic effects of 3‐(5‐nitro‐2‐thienyl)‐9‐chloro‐5‐morpholin‐4‐yl[1,2,4]triazolo[4,3‐c]quinazoline in murine leukemia L1210 cells. Copyright © 2005 John Wiley & Sons, Ltd.