A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer.
Humans
Animals
Mice
bcl-2-Associated X Protein
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Apoptosis
Colonic Neoplasms
/ drug therapy
Antineoplastic Agents
/ pharmacology
Apoptosis Regulatory Proteins
/ metabolism
ErbB Receptors
/ metabolism
Carcinogenesis
Cell Transformation, Neoplastic
Phenols
/ pharmacology
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms
/ drug therapy
EGFR inhibitor
alkylaminophenols
apoptosis
colon cancer
oncogenesis
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
01 2024
01 2024
Historique:
received:
17
04
2023
accepted:
03
05
2023
medline:
6
12
2023
pubmed:
15
5
2023
entrez:
15
5
2023
Statut:
ppublish
Résumé
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. 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. Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC 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.
Sections du résumé
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 IC
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.
Substances chimiques
bcl-2-Associated X Protein
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins c-bcl-2
0
Antineoplastic Agents
0
Apoptosis Regulatory Proteins
0
ErbB Receptors
EC 2.7.10.1
Phenols
0
EGFR protein, human
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107-124Subventions
Organisme : Fundação para a Ciência e a Tecnologia
ID : CEECINST/00026/2018
Organisme : PT National Funds
ID : UIDP/50006/2020
Organisme : PT National Funds
ID : UIDB/50006/2020
Organisme : South African Medical Research Council
Informations de copyright
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Eur J Pharmacol. 2020 Aug 15;881:173195
pubmed: 32446710
Life Sci. 2004 Mar 12;74(17):2157-84
pubmed: 14969719
ChemistryOpen. 2015 Feb;4(1):39-46
pubmed: 25861569
Eur J Med Chem. 2017 May 26;132:108-134
pubmed: 28342939
Chem Rec. 2019 Feb;19(2-3):362-393
pubmed: 29943894
Int J Nanomedicine. 2014;9:461-5
pubmed: 24453488
Br J Pharmacol. 2022 Aug;179(15):3907-3913
pubmed: 35673806
J Med Chem. 2021 Aug 12;64(15):10908-10918
pubmed: 34304559
Mar Drugs. 2013 Oct 11;11(10):3802-22
pubmed: 24152558
Blood. 2005 Jul 15;106(2):690-7
pubmed: 15802533
Br J Cancer. 2010 Sep 7;103(6):861-9
pubmed: 20823889
Chem Biol Drug Des. 2007 Nov;70(5):424-36
pubmed: 17949360
J Biol Chem. 1998 May 1;273(18):10823-6
pubmed: 9556553
Cancer Lett. 2008 Oct 8;269(2):352-62
pubmed: 18472213
Medchemcomm. 2018 Jul 31;9(9):1553-1564
pubmed: 30288229
Cancer Lett. 2009 Feb 18;274(2):299-304
pubmed: 18952370
Cells. 2020 Mar 10;9(3):
pubmed: 32164385
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
pubmed: 10592235
Cells. 2019 Dec 12;8(12):
pubmed: 31842391
Cell Death Dis. 2017 May 25;8(5):e2815
pubmed: 28542135
Mol Cancer. 2007 Jan 18;6:8
pubmed: 17233906
Nucleic Acids Res. 2011 Jul;39(Web Server issue):W270-7
pubmed: 21624888
Orthop Surg. 2009 May;1(2):144-52
pubmed: 22009832
FEBS Lett. 1997 Dec 22;420(1):25-7
pubmed: 9450543
Cell Death Differ. 2002 Jan;9(1):20-6
pubmed: 11803371
Signal Transduct Target Ther. 2020 Mar 20;5(1):22
pubmed: 32296018
Cell Death Differ. 1999 Feb;6(2):99-104
pubmed: 10200555
Front Oncol. 2022 Mar 25;12:869672
pubmed: 35402265
Br J Pharmacol. 2021 Oct;178 Suppl 1:S264-S312
pubmed: 34529829
ChemMedChem. 2016 Sep 20;11(18):2015-23
pubmed: 27457409
Nat Rev Gastroenterol Hepatol. 2019 Dec;16(12):713-732
pubmed: 31455888
World J Surg Oncol. 2015 May 28;13:189
pubmed: 26016480
World J Gastroenterol. 2018 Sep 14;24(34):3834-3848
pubmed: 30228778
J Cancer. 2016 Jun 23;7(10):1250-7
pubmed: 27390600
Br J Pharmacol. 2021 Oct;178 Suppl 1:S1-S26
pubmed: 34529830
Cancer Metastasis Rev. 2008 Mar;27(1):103-18
pubmed: 18049863
Biol Pharm Bull. 1998 Jun;21(6):569-73
pubmed: 9657039
Int J Cancer. 2017 Feb 1;140(3):662-673
pubmed: 27750381
Br J Pharmacol. 2020 Aug;177(16):3611-3616
pubmed: 32662875
Nature. 1997 May 15;387(6630):299-303
pubmed: 9153396
Cell. 1997 Oct 31;91(3):325-34
pubmed: 9363941
Br J Pharmacol. 2018 Feb;175(3):407-411
pubmed: 29350411
Int J Colorectal Dis. 2007 Oct;22(10):1201-8
pubmed: 17390142
World J Gastroenterol. 2017 Jun 28;23(24):4341-4353
pubmed: 28706417
Biochim Biophys Acta. 2009 Apr;1795(2):117-29
pubmed: 19167459
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Anticancer Agents Med Chem. 2017;17(12):1710-1720
pubmed: 28356015
Br J Pharmacol. 2021 Oct;178 Suppl 1:S313-S411
pubmed: 34529828
J Biomol Struct Dyn. 2022 Oct;40(16):7545-7554
pubmed: 33749517
Eur J Med Chem. 2016 Sep 14;120:296-303
pubmed: 27214140
Endocr Relat Cancer. 2006 Jun;13(2):293-325
pubmed: 16728565
Cancer Res. 2004 Oct 15;64(20):7183-90
pubmed: 15492230
Eur J Med Chem. 2018 May 10;151:628-685
pubmed: 29656203
Tumour Biol. 2004 Sep-Dec;25(5-6):258-63
pubmed: 15627889
Cell Death Differ. 2007 Jul;14(7):1237-43
pubmed: 17431418
J Pathol. 2001 Sep;195(2):171-8
pubmed: 11592095
Br J Pharmacol. 2020 Aug;177(16):3617-3624
pubmed: 32662519
Oncogene. 1999 Nov 1;18(45):6145-57
pubmed: 10557106
Free Radic Biol Med. 2017 Mar;104:280-297
pubmed: 28131902
Neoplasma. 2015;62(1):16-26
pubmed: 25563363
Br J Pharmacol. 2024 Jan;181(1):107-124
pubmed: 37183661
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W363-7
pubmed: 15980490