Anticancer activity of THMPP: Downregulation of PI3K/ S6K1 in breast cancer cell line

• Published in: Saudi pharmaceutical journal Vol. 28; no. 4; pp. 495 - 503
• Main Authors: Palanivel, Suresh, Murugesan, Akshaya, Yli-Harja, Olli, Kandhavelu, Meenakshisundaram
• Format: Journal Article
• Language: English
• Published: Saudi Arabia Elsevier B.V 01.04.2020; Elsevier
• Subjects: ADME; Apoptosis; Docking; EGFR; Gene expression; QSAR; Tetrahydroquinoline; PR; ADME; MCF-7; SkBr3; FACS; Gene expression; ER; EGFR; Tetrahydroquinoline; FITC; PI3K; QSAR; IC50; RTPCR; THMPP; ADME-Absorption; Docking; AO/EtBr; Apoptosis; SkBr3, Sloan–Kettering Cancer Center; FACS, Fluorescence-activated cell sorting; QSAR, Quantitative structure activity relationship; PR, Progesterone Receptor; MCF-7, Michigan Cancer Foundation-7; ER, Estrogen Receptor; PI3K, Phosphoinositide 3-kinase; FITC, Fluorescein isothiocyanate; THMPP, 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol; ADME-Absorption, Distribution, Metabolism, and Excretion; IC50, The half maximal inhibitory concentration; AO/EtBr, Acridine orange/ethidium bromide; EGFR, Epidermal Growth Factor Receptor; RTPCR, Reverse Transcriptase PCR
• ISSN: 1319-0164; 2213-7475
• DOI: 10.1016/j.jsps.2020.02.015

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and non-tumorigenic cell line (H9C2) was assessed by MTT assay. THMPP at IC50 concentration of 83.23 μM and 113.94 μM, induced cell death in MCF-7 and SkBr3 cells, respectively. Increased level of caspase-3 and -9, fragmentation of DNA, translocation of phosphatidylserine membrane and morphological changes in the cells confirmed the effect of THMPP in inducing the apoptosis. Gene expression analysis has shown that THMPP was able to downregulate the expression of PI3K/S6K1 genes, possibly via EGFR signaling pathway in both the cell lines, MCF-7 and SkBr3. Further, molecular docking also confirms the potential binding of THMPP with EGFR. QSAR and ADME analysis proved THMPP as an effective anti-breast cancer drug, exhibiting important pharmacological properties. Overall, the results suggest that THMPP induced cell death might be regulated by EGFR signaling pathway which augments THMPP being developed as a potential candidate for treating breast cancer.