Inhibition of Ehrlich ascites cancer, hypoxia-inducible factor-1 alpha, and the kinase insert domain-containing receptor/fms-like tyrosine kinase-binding domains of vascular endothelial growth factor by Thiazole Acetamide Derivatives
LN Madhu1, Sandeep Telkar2, Divyalaxmi Kamath1, Melita Evan D. Souza1, Shama Rao3, Prakash S Nayak4, BK Sarojini5
1 Department of PG Studies and Research in Biochemistry, St. Aloysius College, Mangalore, Karnataka, India
2 Department of PG Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Shimoga, Karnataka, India
3 Nitte University Centre for Stem cell Research and Regenerative Medicine, Nitte University, Mangalore, Karnataka, India
4 Department of Chemistry, Mangalore University, Mangalore, Karnataka, India
5 Department of Industrial Chemistry, Mangalore University, Mangalore, Karnataka, India
Department of PG Studies and Research in Biochemistry, St. Aloysius College, Mangalore - 575 003, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia-inducible factor-1 alpha (HIF-1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative's anticancer property, anti VEGF and HIF-1α inhibitory property were investigated.
Methodology: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich's ascites cancer cells. To evaluate the anticancer property the assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase (FLT)-binding domains of VEGF protein. HIF-1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line.
Results: The study compounds inhibited HIF-1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT-binding domains of VEGF protein.
Conclusion: These results conclude the anticancer and anti-angiogenic property of the synthesized thiazole-acetamide derivatives.