Abstract 398P
Background
Quinacrine (QC) has originally been used as a drug for close to a century. The anti-cancer potential of QC was discovered in a screen for small molecule activators of p53; though, the mechanisms of anti-cancer effects of QC are not well understood. We have discovered binding mechanisms of QC with GSTA1. This finding has been accompanied by a detailed study of the downstream effects of this molecule and novel interaction on the viability of non-small cell lung cancer cells (NSCLC), cell cycle progression, and apoptotic signaling cascades.
Methods
To gain the apoptosis-inducing pathways, the role of QC in cell migration and angiogenesis was studied using both in vitro and xenograft mouse models. Through molecular docking studies, we have shown the potential involvement of QC in the inhibition of receptor and non-receptor kinases. We have shown the binding of QC to the VEGFR2. Through matrigel-based cell migration and angiogenesis assays, we have established the migration nature of QC-treated as well as untreated NSCLC cells. QC causes the generation of ROS leading to ER stress and mitochondria-mediated NSCLC cell death.
Results
QC has promising anticancer potential against NSCLC cells via inhibition of GSTA1, induction of G1/S cell cycle arrest, and ROSmediated apoptotic signaling. MD simulation studies revealed that QC forms a stable interaction with the allosteric site of the kinase domain of VEGFR2 and inhibits their activities. The migration and proliferation of NSCLC cells were inhibited due to the downregulation of crucial migration-promoting proteins.
Conclusions
The inhibitory effects of QC on the activities of VEGFR2 revealed novel aspects of its potential use against oncogenic targets. These findings along with the inhibition of cell migration by QC at the molecular level, further strengthen the potential of QC as a promising treatment avenue for NSCLC.
Funding
Department of Biotechnology, Govt. of India and BITS Pilani, India
Disclosure
The author has declared no conflicts of interest.