Targeting the mutant PIK3CA gene by DNA-alkylating pyrrole-imidazole polyamide in cervical cancer.
Animals
Antineoplastic Agents, Alkylating
/ chemical synthesis
Cell Line, Tumor
Cell Survival
/ drug effects
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Female
Gain of Function Mutation
Humans
Imidazoles
/ chemical synthesis
Mice
Nylons
/ chemical synthesis
Protein Kinase Inhibitors
/ chemical synthesis
Pyrroles
/ chemical synthesis
Uterine Cervical Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
E545K mutation
PI3K inhibitor
PIK3CA gene
cervical cancer
pyrrole-imidazole polyamide-seco-CBI
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
09
10
2020
revised:
17
12
2020
accepted:
23
12
2020
pubmed:
31
12
2020
medline:
18
3
2021
entrez:
30
12
2020
Statut:
ppublish
Résumé
PIK3CA is the most frequently mutated oncogene in cervical cancer, and somatic mutations in the PIK3CA gene result in increased activity of PI3K. In cervical cancer, the E545K mutation in PIK3CA leads to elevated cell proliferation and reduced apoptosis. In the present study, we designed and synthesized a novel pyrrole-imidazole polyamide-seco-CBI conjugate, P3AE5K, to target the PIK3CA gene bearing the E545K mutation, rendered possible by nuclear access and the unique sequence specificity of pyrrole-imidazole polyamides. P3AE5K interacted with double-stranded DNA of the coding region containing the E545K mutation. When compared with conventional PI3K inhibitors, P3AE5K demonstrated strong cytotoxicity in E545K-positive cervical cancer cells at lower concentrations. PIK3CA mutant cells exposed to P3AE5K exhibited reduced expression levels of PIK3CA mRNA and protein, and subsequent apoptotic cell death. Moreover, P3AE5K significantly decreased the tumor growth in mouse xenograft models derived from PIK3CA mutant cells. Overall, the present data strongly suggest that the alkylating pyrrole-imidazole polyamide P3AE5K should be a promising new drug candidate targeting a constitutively activating mutation of PIK3CA in cervical cancer.
Identifiants
pubmed: 33377228
doi: 10.1111/cas.14785
pmc: PMC7935806
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Imidazoles
0
Nylons
0
Protein Kinase Inhibitors
0
Pyrroles
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1141-1149Subventions
Organisme : Ministry of Education, Culture, Sports, Science and Technology
ID : JP25830092
Organisme : Japan Society for the Promotion of Science
ID : JP16H01579
Organisme : Japan Society for the Promotion of Science
ID : JP17H03602
Organisme : Japan Society for the Promotion of Science
ID : JP26290060
Organisme : Princess Takamatsu Cancer Research Fund
Organisme : Takeda Science Foundation
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Références
Sci Rep. 2017 Aug 29;7(1):9842
pubmed: 28852212
J Pharm Sci. 2000 Aug;89(8):1085-96
pubmed: 10906732
J Med Chem. 2013 Sep 26;56(18):7449-57
pubmed: 24015881
Mol Cancer. 2015 Apr 17;14:87
pubmed: 26022660
Mol Cancer. 2011 Jun 10;10:71
pubmed: 21663621
Clin Cancer Res. 2006 Jan 1;12(1):250-6
pubmed: 16397049
Cancer Sci. 2021 Mar;112(3):1141-1149
pubmed: 33377228
Cancer Sci. 2010 Mar;101(3):759-66
pubmed: 20085585
Oncotarget. 2014 Nov 30;5(22):11168-79
pubmed: 25426553
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13175-9
pubmed: 19666554
Cancer Res. 2017 May 1;77(9):2207-2212
pubmed: 28360139
Cancer Cell. 2011 Jan 18;19(1):58-71
pubmed: 21215704
J Am Soc Nephrol. 2006 Feb;17(2):422-32
pubmed: 16371433
Clin Cancer Res. 2016 Apr 15;22(8):2009-19
pubmed: 26589432
Cancer Sci. 2015 Apr;106(4):421-9
pubmed: 25611295
Mol Cancer Ther. 2014 Nov;13(11):2477-88
pubmed: 25323681
Int J Cancer. 2015 Mar 1;136(5):E359-86
pubmed: 25220842
Cancer. 2013 Nov 1;119(21):3776-83
pubmed: 24037752
Nat Rev Clin Oncol. 2013 Mar;10(3):143-53
pubmed: 23400000
Nat Rev Cancer. 2009 Aug;9(8):550-62
pubmed: 19629070
Chemistry. 2014 Jan 27;20(5):1310-7
pubmed: 24382626
Oncogene. 2011 Jun 2;30(22):2547-57
pubmed: 21278786
Clin Cancer Res. 2017 Jan 1;23(1):26-34
pubmed: 27126994
Cancer Cell. 2003 May;3(5):483-95
pubmed: 12781366
J Org Chem. 2011 Jan 21;76(2):583-7
pubmed: 21192653
Acc Chem Res. 2006 Dec;39(12):935-44
pubmed: 17176032
Chem Biol. 2014 Oct 23;21(10):1370-1380
pubmed: 25219965
Mol Cancer Ther. 2018 May;17(5):988-1002
pubmed: 29483218
Oncotarget. 2016 Dec 13;7(50):82424-82439
pubmed: 27489350
Curr Opin Struct Biol. 2003 Jun;13(3):284-99
pubmed: 12831879
Sci Rep. 2017 Aug 31;7(1):10240
pubmed: 28860563
Nucleic Acids Res. 2006 Feb 25;34(4):1189-95
pubmed: 16500890
Nature. 2013 Oct 17;502(7471):333-339
pubmed: 24132290
Bioconjug Chem. 2006 May-Jun;17(3):715-20
pubmed: 16704209
Chem Biol. 2000 Mar;7(3):153-61
pubmed: 10712931
PLoS One. 2016 Oct 31;11(10):e0165581
pubmed: 27798693
Int J Cancer. 2006 Apr 15;118(8):1877-83
pubmed: 16287065
J Clin Oncol. 2009 Oct 1;27(28):4649-55
pubmed: 19720909
Nat Commun. 2015 Apr 27;6:6706
pubmed: 25913614