In vivo antitumor activity of FK-A11, a depsipeptide analog targeting both histone deacetylase and phosphoinositide 3-kinase

Aim/Background

Histone deacetylase (HDAC) inhibitors are actively explored as new-generation epigenetic drugs for cancer therapy. Phosphoinositide 3-kinase (PI3K) is also pursued as anti-cancer target. Because the combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy. We have previously identified romidepsin (FK228, depsipeptide) and its analogs as HDAC/PI3K dual inhibitors and found that FK-A11 was the most potent analog. This study investigated the anti-tumor activity of FK-A11.

Methods

We have tested, in vitro and in vivo, the effects of FK-A11 and other analogs in human prostate cancer cell, PC-3. MTT assay was employed to analyze the cytotoxic effect of FK-A11 in vitro. PC-3 xenograft-bearing nude mice were used to assess the anti-tumor activity of FK-A11. Phosphorylation of AKT and acetylation of histone were assayed by western blotting in vitro and by immunohistochemistry in vivo.

Results

FK-A11 simultaneously inhibited phosphorylation of AKT and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than FK228 and the other analogs in PC-3 cells. FK-A11 administrated intra-peritoneally showed antitumor activity, reduced AKT phosphorylation and increased histone acetylation in the PC-3 xenografts in mice.

Conclusions

We demonstrated that FK-A11 is a novel HDAC/PI3K dual inhibitor and that it has antitumor activity against human cancer xenografts. These finding showed that FK-A11 could be an attractive therapeutic strategy for cancer therapy.

Clinical trial identification

none

Disclosure

C. Ishioka: research funding from Tokyo Cooperative Oncology Group, and contributions from Chugai Pharma, Daiichi Sankyo Company, and Taiho Pharma. C.Ishioka represents Tohoku Clinical Oncology Research and Education Society. All other authors have declared no conflicts of interest.