LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK-A11

Hiroo Imai, Ken Saijo, Sonoko Chikamatsu, Yoshifumi Kawamura, Chikashi Ishioka

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphatidylinositol-3 kinase (PI3K) inhibitor and histone deacetylase (HDAC) inhibitor have been developed as potential anticancer drugs. However, the cytotoxicity of PI3K inhibitor or HDAC inhibitor alone is relatively weak. We recently developed a novel HDAC/PI3K dual inhibitor FK-A11 and confirmed its enhanced cytotoxicity when compared to that of PI3K inhibitor or HDAC inhibitor alone on several cancer cell lines. However, the in vivo antitumor activity of FK-A11 was insufficient. We conducted high-throughput RNA interfering screening and identified gene LPIN1 which enhances the cytotoxicity of FK-A11. Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK-A11 and enhanced the cytotoxicity of FK-A11. Propranolol, a beta-adrenoreceptor which is also a LPIN1 inhibitor, enhanced the in vitro and in vivo cytotoxicity and antitumor effect of FK-A11. These findings should help in the development of FK-A11 as a novel HDAC/PI3K dual inhibitor.

Original languageEnglish
Pages (from-to)792-802
Number of pages11
JournalCancer science
Volume112
Issue number2
DOIs
Publication statusPublished - 2021 Feb

Keywords

  • LPIN1
  • dual HDAC/PI3K inhibitor
  • histone deacetylase
  • phosphatidylinositol-3 kinase
  • propranolol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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