Open AccessAntitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3‐kinase dual inhibitor
Author(s) -
Saijo Ken,
Imai Hiroo,
Chikamatsu Sonoko,
Narita Koichi,
Katoh Tadashi,
Ishioka Chikashi
Publication year - 2017
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.13255
Subject(s) - depsipeptide , romidepsin , histone deacetylase , in vivo , pharmacology , histone deacetylase inhibitor , chemistry , cancer research , medicine , biology , biochemistry , histone , microbiology and biotechnology , gene
Histone deacetylase ( HDAC )/phosphatidylinositol 3‐kinase ( PI 3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC / PI 3K dual inhibitor is reasonably attractive. Romidepsin ( FK 228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI 3K inhibitors and are defined as HDAC / PI 3K dual inhibitors. Subsequently, we identified FK ‐A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC / PI 3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK ‐A11 in HT 1080 fibrosarcoma and PC 3 prostate cancer cell xenograft mouse models. FK ‐A11 showed in vivo antitumor activity by both i.v. and i.p. administration in a dose‐dependent manner. In both xenograft models, FK ‐A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti‐cell proliferation effects and the potency of HDAC / PI 3K dual inhibition. In addition, we showed evidence of HDAC / PI 3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK ‐A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.