RRC ID 77040
Author Krishnamurthy S, Yoda H, Hiraoka K, Inoue T, Lin J, Shinozaki Y, Watanabe T, Koshikawa N, Takatori A, Nagase H.
Title Targeting the mutant PIK3CA gene by DNA-alkylating pyrrole-imidazole polyamide in cervical cancer.
Journal Cancer Sci
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.
Volume 112(3)
Pages 1141-1149
Published 2021-3-1
DOI 10.1111/cas.14785
PMID 33377228
PMC PMC7935806
MeSH Animals Antineoplastic Agents, Alkylating / chemical synthesis Antineoplastic Agents, Alkylating / pharmacology* Antineoplastic Agents, Alkylating / therapeutic use Cell Line, Tumor Cell Survival / drug effects Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors* Class I Phosphatidylinositol 3-Kinases / genetics Female Gain of Function Mutation Humans Imidazoles / chemical synthesis Imidazoles / pharmacology Imidazoles / therapeutic use Mice Nylons / chemical synthesis Nylons / pharmacology Protein Kinase Inhibitors / chemical synthesis Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Pyrroles / chemical synthesis Pyrroles / pharmacology Pyrroles / therapeutic use Uterine Cervical Neoplasms / drug therapy* Uterine Cervical Neoplasms / genetics Uterine Cervical Neoplasms / pathology Xenograft Model Antitumor Assays
IF 4.966
Human and Animal Cells ME-180(RCB2160) Ca Ski(RCB1947)