Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor
| Autor: | Chikashi Ishioka, Ken Saijo, Tadashi Katoh, Hiroo Imai, Koichi Narita, Sonoko Chikamatsu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Blotting Western Mice Nude PI3K Romidepsin Mice 03 medical and health sciences 0302 clinical medicine HDAC In vivo Cell Line Tumor Depsipeptides medicine romidepsin Animals Humans PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Depsipeptide Mice Inbred BALB C Chemistry Kinase Original Articles Neoplasms Experimental General Medicine Immunohistochemistry Xenograft Model Antitumor Assays In vitro Histone Deacetylase Inhibitors Drug Discovery and Delivery 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Original Article HT1080 Dual inhibitor Histone deacetylase pharmacokinetics medicine.drug |
| Zdroj: | Cancer Science |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/cas.13255 |
| Popis: | Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) 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/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 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/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K 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. |
| Databáze: | OpenAIRE |
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