84P - Quinacrine inhibits angiogenesis and migration of non-small cells lung cancer cells (NSCLC) by binding with the kinase domain of VEGFR2

Background

The potential of a small molecule ‘quinacrine’ (QC) is to simultaneously target multiple signaling cascades and cellular processes that are implicated in promoting carcinogenesis, is indeed a beneficial factor, adding a unique aspect to its scope of utility for cancer treatment. From our laboratory we have already shown QCs activity against non-small cell lung cancer (NSCLC) and the underlying mechanisms that revolves around the activation of the tumor protein 53 (p53) signaling pathway and initiation of mitochondrial damage. Cancer metastasis, which is the hallmark feature of malignant tumors, is a complex, multi-step process. Therefore, we thought to investigate the role of QC in targeting this very process.

Methods

In this report we have studied the mechanisms that involved in the binding of QC to the vascular endothelial growth factor receptor 2 (VEGFR2) using a molecular docking approach. Matrigel-based cell migration and angiogenesis assays were carried out to assess the migration activity of NSCLC cells. We also explored its potential involvement in the inhibition of receptor and non-receptor kinases, which play essential roles in cancer progression.

Results

Various molecular dynamics (MD) simulation studies revealed that QC forms a stable interaction with the allosteric site of the kinase domain of VEGFR2 and inhibits their activities. QC was found to bind to VEGFR2 via hydrogen bond interactions with the residues aspartic acid 814 (Asp 814) and aspartic acid 1046 (Asp 1046), water bridge interactions via glutamic acid 885 (Glu 885), and hydrophobic interactions via isoleucine 888 (Ile 888). QC significantly inhibited the VEGF-induced proliferation of cells of both NSCLC cell lines, A549 and NCI H520. 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.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

A. Sarkar.

Funding

DBT Govt. of India and BITS Pilani.

Disclosure

The author has declared no conflicts of interest.