Alkylamino Phenol Derivative Induces Apoptosis by Inhibiting EGFR Signaling Pathway in Breast Cancer Cells

Abstract

<jats:sec> <jats:title>Background and Objective:</jats:title> <jats:p>The present study was carried out to evaluate the anticancer property of an alkylamino phenol derivative -2-((3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol) (THTMP) against human breast cancer cells. The cytotoxicity of the THTMP was assessed to know its specificity towards breast cancer cells without affecting the normal cells.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>The THTMP was synthesized and the cytotoxicity was assessed by MTT assay, Caspases enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR and QSAR. In addition, ADME analysis was executed to understand the mode of action of THTMP.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>THTMP showed potential cytotoxic activity against the growth of MCF7 and SK-BR3 cells with the IC50 values of 87.92μM and 172.51μM, respectively. Interestingly, THTMP found to activate caspase 3 and caspase 9 enzymes in cancer cells, which are the key enzymes implicated in apoptosis. THTMP induced apoptosis in which 33% of the cells entered the late apoptotic stage after 24h of treatment. The results also revealed that the apoptotic response could be influenced by the association of THTMP with the Epidermal Growth Factor Receptor (EGFR) mediated inhibition of the Phosphatidylinositol 3-Kinase (PI3K)/S6K1 signaling pathway. In addition, docking was performed to study the binding mode of the THTMP, which shows better interaction with EGFR. The structural elucidation of THTMP by Quantitative Structure-Activity Relationship model (QSAR) and ADMET screening suggested, THTMP as an effective anticancer compound.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>This work strengthens the potential of a promising drug-like compound, THTMP, for the discovery of anticancer drug against breast cancer.</jats:p> </jats:sec>

Novel Derivatives of 4,6‐Dihydroxy‐2‐Quinolone‐3‐Carboxamides as Potential PI3Kα Inhibitors

“…Biological testing showed that phenolic motif exerts chemopreventive activity (anticancer, antioxidant, and anti‐inflammatory effects) [16] targeting PI3K signaling cascade, [17] sphingosine kinase, [18] dihydroceramide desaturase, [18] epidermal growth factor receptor (EGFR), [19] phosphatase and tensin homolog (PTEN), [20] protein kinase B (AKT), [17c,20] hypoxia‐inducible factor‐1 (HIF‐1α), [20] vascular endothelial growth factor (VEGF), [20] toll‐like receptor (TLR4), [21] mammalian target of rapamycin (mTOR), [21] wingless (Wnt), [22] nuclear factor kappa B (NF‐κB), [22] and Glycogen synthase kinase‐3β (GSK‐3β) [17c] pathways. Further studies demonstrated that phenolic moiety exhibits…”