Open AccessLPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK‐A11
Author(s) -
Imai Hiroo,
Saijo Ken,
Chikamatsu Sonoko,
Kawamura Yoshifumi,
Ishioka Chikashi
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14759
Subject(s) - cytotoxicity , histone deacetylase inhibitor , downregulation and upregulation , pi3k/akt/mtor pathway , pharmacology , in vivo , histone deacetylase , chemistry , cancer research , biology , in vitro , biochemistry , histone , signal transduction , gene , microbiology and biotechnology
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.