Publication: A novel EGFR Inhibitor, HNPMI regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer.
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2023-05-14T21:00:00Z
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Kandhavelu, Jeyalakshmi
Subramanian, Kumar
Naidoo, Vivash
Sebastianelli, Giulia
Doan, Phuong
Mani, Saravanan Konda
Yapislar, Hande
Haciosmanoglu, Ebru
Arslan, Leman
Ozer, Samed
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Abstract
Colorectal cancer (CRC) is the second most devastating disease leading to higher mortality due to its heterogeneity and chemo-resistance. Epidermal growth factor receptor (EGFR) is an effective therapeutic target and the focus of this study. Polyphenols modulate several key signaling mechanisms including EGFR-signaling associated with anti-proliferative and anti-metastatic properties.
Using ligand- and structure-based cheminformatics we developed three potent, selective alkylaminophenols, THTMP, THMPP, and HNPMI. These alkylaminophenols, were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation, transcriptional and translational regulation. Finally, lead compound was evaluated for efficacy in the xenograft mice model.
We identify that alkylaminophenols as an effective anti-EGFR compound against different grades of CRC. HNPMI exhibited the least IC on CRC cells and potential cytotoxicity effect on other tumour cells too. Modulation of EGFR pathway downregulated the osteopontin, survinin and cathepsin S proteins, thus leading to apoptosis. Furthermore, cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered several apoptotic-related proteins including Caspase 3, BCL-2, and p53, which were also validated at the level of RNA and protein. HNPMI significantly downregulated the crucial proteins associated with oncogenesis in CRC cells. Further, pre-clinical validation in xenograft mice confirmed the potential of HNPMI in reducing the relative tumor volume.
HNPMI is the promising EGFR inhibitor for clinical translation. HNPMI regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC, thus suggesting it as a therapeutic drug target for treating CRC.
Using ligand- and structure-based cheminformatics we developed three potent, selective alkylaminophenols, THTMP, THMPP, and HNPMI. These alkylaminophenols, were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation, transcriptional and translational regulation. Finally, lead compound was evaluated for efficacy in the xenograft mice model.
We identify that alkylaminophenols as an effective anti-EGFR compound against different grades of CRC. HNPMI exhibited the least IC on CRC cells and potential cytotoxicity effect on other tumour cells too. Modulation of EGFR pathway downregulated the osteopontin, survinin and cathepsin S proteins, thus leading to apoptosis. Furthermore, cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered several apoptotic-related proteins including Caspase 3, BCL-2, and p53, which were also validated at the level of RNA and protein. HNPMI significantly downregulated the crucial proteins associated with oncogenesis in CRC cells. Further, pre-clinical validation in xenograft mice confirmed the potential of HNPMI in reducing the relative tumor volume.
HNPMI is the promising EGFR inhibitor for clinical translation. HNPMI regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC, thus suggesting it as a therapeutic drug target for treating CRC.