LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK‐A11. Issue 2 (8th January 2021)

• Record Type: Journal Article
• Authors: Imai, Hiroo; Saijo, Ken; Chikamatsu, Sonoko; Kawamura, Yoshifumi; Ishioka, Chikashi
• Is Part Of: Cancer science. Volume 112:Issue 2(2021)
• Page Start: 792
• Page End: 802
• Publication Date: 2021-01-08
• Subjects: dual HDAC/PI3K inhibitor -- histone deacetylase -- LPIN1 -- phosphatidylinositol‐3 kinase -- propranolol; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14759
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : High throughput gene suppression screening identified LPIN1 gene as the potential target that enhances the cytotoxicity of novel HDAC/PI3K dual inhibitor, FK‐A11. Treatment with propranolol, which is the LPIN1 inhibitor, significantly enhanced the antitumor effect of FK‐A11 in vivo.