Vakamullu Sridhar, Arepalli S K, Velatooru L R, J Venkateswara Rao, P Kavin Kennedy, B Narsaiah
Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India; MNR Foundation for Research and Innovation, MNR Medical College, Sangareddy, Telangana, 502294, India.
Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India.
Chem Biol Interact. 2018 Jan 25;280:117-127. doi: 10.1016/j.cbi.2017.12.015. Epub 2017 Dec 8.
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 (IC0.66 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, IC62.17 μg/ml). Based on the results we suggest that DMQA induced apoptosis via intrinsic pathway and could be a promising anticancer agent.
已发现几种喹唑啉衍生物具有广泛的生物活性。此前，我们的研究小组合成并研究了N-癸基-N-(2-甲基-4-喹唑啉基)胺(DMQA)的抗增殖作用。本研究评估了DMQA在THP-1细胞中的细胞毒性和凋亡特性。使用MTT法在一组癌细胞系上评估DMQA的细胞毒性潜力，这些癌细胞系包括HeLa、Mia PaCa-2、A 375、B16-F10、A 549、A 431、U937、THP-1、HL-60和外周血单个核细胞(PBMC)。初步数据显示，最高的细胞毒性活性针对THP-1白血病细胞系(IC0.66μg/ml)。DMQA对THP-1细胞的凋亡特性通过核形态变化、DNA片段化、前半胱天冬酶-3、9、Bax/Bcl-2水平降低、聚(ADP-核糖)聚合酶的切割和细胞色素c的胞质释放来表征。进一步研究发现THP-1细胞中出现亚G1峰、磷脂酰丝氨酸暴露和线粒体膜电位(MMP)丧失。半胱天冬酶的作用至关重要，抑制剂Z-VAD-FMK和Z-DEVD-FMK证明了这一点。此外，DMQA在抑制正常细胞(PBMC，IC62.17μg/ml)生长方面明显效果较差。基于这些结果我们认为，DMQA通过内源性途径诱导凋亡，可能是一种有前景的抗癌药物。
