In vitro apoptotic mechanism of a novel synthetic Quinazolinyl derivative: Induces caspase-dependent intrinsic pathway on THP-1, leukemia cell line

• Published in: Chemico-biological interactions 2018-01, Vol.280, p.117-127
• Main Authors: Vakamullu, Sridhar, Arepalli, S.K., Velatooru, L.R., J., Venkateswara Rao, P., Kavin Kennedy, B., Narsaiah
• Format: Article
• Language: English
• Subjects: Apoptosis; Caspases; Leukemia cells; Membrane potential; Morphology; Quinazolinyl derivative
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2017.12.015

Several quinazoline derivatives have been found to possess a broad spectrum of biological activities. Previously our research group has synthesized and studied the anti-proliferative effects of N-Decyl-N-(2-Methyl-4-Quinazolinyl) Amine (DMQA). The current study evaluated the cytotoxic and apoptotic properties of DMQA in THP-1 cells. The cytotoxic potential of DMQA was assessed using MTT assay on a panel of cancer cell lines which include HeLa, Mia PaCa-2, A 375, B16-F10, A 549,A 431, U937, THP-1, HL-60 and peripheral blood mononuclear cells (PBMC's). Preliminary data revealed that the highest cytotoxic activity was against THP-1 leukemia cell line (IC50=0.66 μg/ml). The apoptotic properties of DMQA on THP-1 cells were characterized by change in nuclear morphology, DNA fragmentation, reduction of pro-caspases-3, 9, Bax/Bcl-2 levels, cleavage of poly (ADP-ribose) polymerase and cytosolic release of cytochrome c. Further investigation revealed a sub-G1 peak, phosphatidyl serine exposure and loss of mitochondrial membrane potential (MMP) in THP-1 cells. The role of caspases was crucial and was demonstrated by the inhibitors Z-VAD-FMK and Z-DEVD-FMK. Moreover DMQA was markedly less effective in inhibiting the growth of normal cells (PBMC's, IC50 =62.17 μg/ml). Based on the results we suggest that DMQA induced apoptosis via intrinsic pathway and could be a promising anticancer agent. •DMQA induced apoptosis via intrinsic pathway in THP-1 leukemia cells.•DMQA was markedly less effective in inhibiting the growth of normal cells.•The role of caspases was demonstrated by the inhibitors Z-VAD-FMK and Z-DEVD-FMK.