A novel quinazolinone derivative induces cytochrome c interdependent apoptosis and autophagy in human leukemia MOLT-4 cells

Toxicology Reports

Anup Singh Pathania¹  Nagaraju Mupparapu¹  Santosh Kumar Guru¹  Qazi Naveed Ahmed¹  Sandip B. Bharate¹  Fayaz Malik¹  Ram A. Vishwakarma¹  Suresh Kumar¹  Shashi Bhushan¹  Ajay Kumar² 

[1] Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India;Cancer Pharmacology Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;

关键词: 2,3-Dihydro-2-(quinoline-5-yl) quinazolin-4(1H)-one structure [DQQ];    Autophagy;    Apoptosis;    Cytochrome c;    Caspase;   

DOI  :  10.1016/j.toxrep.2014.07.018

来源: DOAJ

【 摘 要 】

Crosstalk between apoptosis and autophagy is budding as one of the novel strategies in the cancer therapeutics. The present study tinted toward the interdependence of autophagy and apoptosis induce by a novel quinazolinone derivative 2,3-dihydro-2-(quinoline-5-yl) quinazolin-4(1H)-one structure [DQQ] in human leukemia MOLT-4 cells. DQQ induces cytochrome c arbitrated apoptosis and autophagy in MOLT-4 cells. Apoptosis induces by DQQ was confirmed through a battery of assay e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis, loss of mitochondrial membrane potential and immune-expression of cytochrome c, caspases and PARP. Furthermore, acridine orange staining, LC3 immunofluorescence and western blotting of key autophagy proteins revealed the autophagic potential of DQQ. A universal caspase inhibitor, Z-VAD-FMK and cytochrome c silencing, strongly inhibited the DQQ induce autophagy and apoptosis. Beclin1 silencing through siRNA partially reversed the cell death, which was not as significant as by cytochrome c silencing. Although, it partially reversed the PARP cleavage induced by DQQ, indicating the role of autophagy in the regulation of apoptosis. The present study first time portrays the negative feedback potential of cytochrome c regulated autophagy and the importance of quinazolinone derivative in discovery of novel anticancer therapeutics.

【 授权许可】

Unknown