Research Papers:
Quinacrine induces apoptosis in cancer cells by forming a functional bridge between TRAIL-DR5 complex and modulating the mitochondrial intrinsic cascade
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Abstract
Sarita Das1, Neha Tripathi2, Ranjan Preet1, Sumit Siddharth1, Anmada Nayak1, Prasad V. Bharatam2, Chanakya Nath Kundu1
1Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Patia, Bhubaneswar, Odisha, 751024, India
2National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India
Correspondence to:
Chanakya Nath Kundu, email: [email protected]
Keywords: quinacrine (QC), tumor necrosis factor related apoptosis inducing ligand (TRAIL), death receptor (DR5), breast cancer, apoptosis
Received: March 23, 2016 Accepted: August 09, 2016 Published: August 17, 2016
ABSTRACT
Death Receptor 5 (DR5) is known to be an important anti-cancer drug target. TRAIL is a natural ligand of DR5, but its drug action is limited because of several factors. A few agonistic ligands were identified as TRAIL-DR5 axis modulators, which enhance the cellular apoptosis. Literature suggest that quinacrine (QC) acts as a DR5 agonistic ligand. However, the detailed mechanism explaining how QC interacts with TRAIL-DR5 axis has not been established. Also focused in vitro and in vivo experimental analysis to validate the hypothesis is not yet performed. In this work, extensive studies have been carried out using in silico analysis (molecular dynamics), in vitro analysis (cell based assays) and in vivo analysis (based on mice xenograft model), to delineate the mechanism of QC action in modulating the TRAIL-DR5 signaling. The MD simulations helped in identifying the important residues contributing to the formation of a QC-TRAIL-DR5 complex, which provide extra stability to it, consequently leading to the enhanced cellular apoptosis. QC caused a dose dependent increase of DR5 expression in cancer cells but not in normal breast epithelial cells, MCF-10A. QC showed a synergistic effect with TRAIL in causing cancer cell apoptosis. In DR5-KD MCF-10A-Tr (DR5 knocked down) cells, TRAIL+ QC failed to significantly increase the apoptosis but over expression of full length DR5 in DR5-silence cells induced apoptosis, further supporting DR5 as a drug target for QC. An increase in the release of reactive species (ROS and RNS) and activation of enzymes (FADD, CASPASES 3, 8, 9 and cytochrome-C) indicated the involvement of mitochondrial intrinsic pathway in TRAIL+QC mediated apoptosis. In vivo study pointed out that TRAIL+QC co-administration increases the expression of DR5 and reduce the tumor size in xenograft mice. This combined in silico, in vitro and in vivo analysis revealed that QC enhances the cellular apoptosis via the modulation of TRAIL-DR5 complexation and the mitochondrial intrinsic pathway.
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