Histone deacetylase inhibitor 2-hexyl-4-pentynoic acid enhances hydroxyurea therapeutic effect in triple-negative breast cancer cells

Chenxia Ding, Benyu Su, Qiaoling Li, Wenwen Ding, Guochao Liu, Zuchao Cai, Fengmei Zhang, David Lim, Zhihui Feng

Research output: Contribution to journalArticlepeer-review

Abstract

Triple-negative breast cancer (TNBC) treatment has only limited effect, and it causes a significant number of deaths. Histone deacetylase inhibitors (HDACis) are emerging as promising anti-tumor agents in many types of cancers. We thus hypothesized that 2-hexyl-4-pentynoic acid (HPTA), a novel HDACi, could sensitize TNBC to hydroxyurea (HU, a ribonucleotide reductase inhibitor). In the present study, we investigated the effect of HPTA, alone or in combination with HU on cell survival, DNA double-strand breaks (DSBs), key homologous recombination (HR) repair proteins and cell cycle progression in MDA-MB-468 and MDA-MB-231 human TNBC cell lines. HPTA and HU synergistically inhibited the survival of TNBC cell lines and resulted in the accumulation of DNA double-strand breaks (DSBs). HPTA can sensitize TNBC cells to HU by inhibiting replication protein A2 (RPA2) hyperphosphorylation-mediated HR repair, and lessen cell accumulation in S-phase by inhibiting ATR-CHK1 signaling pathway. Taken together, our data suggested that HPTA enhances HU therapeutic effect by blocking the HR repair and regulating cell cycle progression in TNBC.

Original languageEnglish
Article number503422
Number of pages9
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume873
DOIs
Publication statusPublished - Jan 2022
Externally publishedYes

Keywords

  • 2-hexyl-4-pentynoic acid
  • Cell cycle
  • Homologous recombination repair
  • Hydroxyurea
  • Triple-negative breast cancer

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