Back to Search
Start Over
Targeting the mutant PIK3CA gene by DNA‐alkylating pyrrole‐imidazole polyamide in cervical cancer
- Source :
- Cancer Science
- Publication Year :
- 2021
- Publisher :
- John Wiley and Sons Inc., 2021.
-
Abstract
- 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.<br />The present study proposes a new promising alkylating PI polyamide, P3AE5K, to target the E545K mutation in PIK3CA. P3AE5K showed high sequence‐specific binding affinity to its target nucleotide sequence, and downregulated the mutant PIK3CA expression and reduced tumor growth in a mouse xenograft tumor model of cervical cancer.
- Subjects :
- 0301 basic medicine
Cancer Research
Somatic cell
cervical cancer
Cell Survival
Class I Phosphatidylinositol 3-Kinases
Mutant
Uterine Cervical Neoplasms
PI3K inhibitor
pyrrole‐imidazole polyamide‐seco‐CBI
medicine.disease_cause
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Pyrroles
Cytotoxicity
neoplasms
Antineoplastic Agents, Alkylating
Protein Kinase Inhibitors
Mutation
Oncogene
Cell growth
Imidazoles
General Medicine
Original Articles
E545K mutation
PIK3CA gene
Molecular biology
Xenograft Model Antitumor Assays
Nylons
030104 developmental biology
Drug Discovery and Delivery
Oncology
chemistry
Apoptosis
030220 oncology & carcinogenesis
Gain of Function Mutation
Original Article
Female
DNA
Subjects
Details
- Language :
- English
- ISSN :
- 13497006 and 13479032
- Volume :
- 112
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cancer Science
- Accession number :
- edsair.doi.dedup.....aaa96551b546b48f72aabcd8659aebd9