A phthalimidoalkanamide derived novel DNMT inhibitor enhanced radiosensitivity of A549 cells by inhibition of homologous recombination of DNA damage

Hyun Cheol Kang, Eui Kyu Chie, Hak Jae Kim, Jin Ho Kim, Il Han Kim, Kwangsoo Kim, Beom Su Shin, Eun Sook Ma

Research output: Contribution to journalArticle

Abstract

Purpose To elucidate the radiosensitizing effect and underlying mechanism of a new kind of DNA methyltransferase (DNMT) inhibitor with biological availability. Methods A novel non-nucleoside compound, designated as MA-17, was recently derived from a phthalimido alkanamide structure. DNMT expressions were confirmed in cultured human lung cancer (A549) and normal astrocyte (NHA) cells, radiosensitivity was measured using clonogenic assay, and assays of cell cycle alteration, apoptosis, DNA damage repair, and differential gene expression were undertaken. Results MA-17 significantly radiosensitized A549 cells with a mean dose enhancement ratio (DER) of 1.43 at the surviving fraction of 0.2 (p < 0.05 by one-tailed ratio paired t-test). MA-17 did not affect normal astrocytes (mean DER0.2, 1.016; p = 0.420). MA-17 demonstrated a mean half-life of 1.0 h in vivo and a relatively even distribution in various tissues. Pretreatment with MA-17 increased sub-G1 fractions and inhibited the repair of DNA double-strand breaks, which are induced by irradiation. We found that MA-17 also down-regulated DNA homologous recombination and the Fanconi anemia pathway (FANCA, BRCA1, and RAD51C) in A549 cells. This bioinformatics finding was confirmed in validation Western blot to evaluate the expression of vital proteins. Conclusions A novel phthalimido alkanamide derivative, a DNMT inhibitor, possessed both biostability and favorable and substantial radiosensitizing effects by augmenting apoptosis or inhibiting DNA damage repair.

Original languageEnglish
Pages (from-to)1158-1165
Number of pages8
JournalInvestigational New Drugs
Volume37
Issue number6
DOIs
StatePublished - 1 Dec 2019

Keywords

  • Cancer
  • DNMT inhibitor
  • Epigenetics
  • Radiosensitization

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