A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:181 |
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| Enthalten in: |
British journal of pharmacology - 181(2024), 1 vom: 03. Jan., Seite 107-124 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kandhavelu, Jeyalakshmi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.12.2023 Date Revised 22.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bph.16141 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM356864170 |
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| 100 | 1 | |a Kandhavelu, Jeyalakshmi |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 22.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a EGFR inhibitor | |
| 650 | 4 | |a alkylaminophenols | |
| 650 | 4 | |a apoptosis | |
| 650 | 4 | |a colon cancer | |
| 650 | 4 | |a oncogenesis | |
| 650 | 7 | |a bcl-2-Associated X Protein |2 NLM | |
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| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
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| 700 | 1 | |a Konda Mani, Saravanan |e verfasserin |4 aut | |
| 700 | 1 | |a Yapislar, Hande |e verfasserin |4 aut | |
| 700 | 1 | |a Haciosmanoglu, Ebru |e verfasserin |4 aut | |
| 700 | 1 | |a Arslan, Leman |e verfasserin |4 aut | |
| 700 | 1 | |a Ozer, Samed |e verfasserin |4 aut | |
| 700 | 1 | |a Thiyagarajan, Ramesh |e verfasserin |4 aut | |
| 700 | 1 | |a Candeias, Nuno R |e verfasserin |4 aut | |
| 700 | 1 | |a Penny, Clement |e verfasserin |4 aut | |
| 700 | 1 | |a Kandhavelu, Meenakshisundaram |e verfasserin |4 aut | |
| 700 | 1 | |a Murugesan, Akshaya |e verfasserin |4 aut | |
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