2. Academic Validation
  3. A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer

  • Br J Pharmacol. 2024 Jan;181(1):107-124. doi: 10.1111/bph.16141.
Jeyalakshmi Kandhavelu 1,  Kumar Subramanian 1,  Vivash Naidoo 1,  Giulia Sebastianelli 2,  Phuong Doan 2 3 4,  Saravanan Konda Mani 5,  Hande Yapislar 6,  Ebru Haciosmanoglu 7,  Leman Arslan 8,  Samed Ozer 6,  Ramesh Thiyagarajan 9,  Nuno R Candeias 10 11,  Clement Penny 1,  Meenakshisundaram Kandhavelu 2 3 4,  Akshaya Murugesan 2 12
Affiliations

Affiliations

  • 1 Division of Oncology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
  • 2 Molecular Signalling Lab, Faculty of Medicine and Health Technology, BioMediTech, Tampere University and Tays Cancer Centre, Tampere, Finland.
  • 3 BioMediTech Institute and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
  • 4 Science Center, Tampere University Hospital, Tampere, Finland.
  • 5 Research and Publication Wing, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, India.
  • 6 Department of Physiology, Acibadem University School of Medicine, Atasehir, Istanbul, Turkey.
  • 7 Department of Biophysics, Bezmialem Vakıf University School of Medicine, Fatih, Istanbul, Turkey.
  • 8 Department of Physiology, Bezmialem Vakıf University School of Medicine, Fatih, Istanbul, Turkey.
  • 9 Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia.
  • 10 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
  • 11 Faculty of Engineering and Natural Sciences, Tampere University, Tampere, Finland.
  • 12 Department of Biotechnology, Lady Doak College, Thallakulam, Madurai, India.
PMID: 37183661 DOI: 10.1111/bph.16141
Abstract

Background and purpose: Colorectal Cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of Polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties.

Experimental approach: Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and Apoptosis induction, Caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells.

Key results: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, Survivin and Cathepsin S, leading to Apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including Caspase 3, Bcl-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume.

Conclusions and implications: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated Apoptosis and oncogenesis by modulating Bcl-2/Bax and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.

Keywords

EGFR inhibitor; alkylaminophenols; apoptosis; colon cancer; oncogenesis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162148
    EGFR Inhibitor