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

Author:

Kandhavelu Jeyalakshmi1,Subramanian Kumar1,Naidoo Vivash1,Sebastianelli Giulia2,Doan Phuong234,Konda Mani Saravanan5ORCID,Yapislar Hande6,Haciosmanoglu Ebru7,Arslan Leman8,Ozer Samed6,Thiyagarajan Ramesh9,Candeias Nuno R.1011,Penny Clement1,Kandhavelu Meenakshisundaram234ORCID,Murugesan Akshaya212

Affiliation:

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

Abstract

AbstractBackground and PurposeColorectal 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 ApproachUsing 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 ResultsOf 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 ImplicationsHNPMI 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.

Funder

Fundação para a Ciência e a Tecnologia

South African Medical Research Council

Publisher

Wiley

Subject

Pharmacology

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