Differential immunotoxicity of histone deacetylase inhibitors on malignant and naïve hepatocytes

Abstract

Western blot analysis showed that all HDIs studied downregulated the anti-apoptotic protein cFLIP, but only VPA additionally affected the expression level of XIAP. Furthermore, in models of the intrinsic apoptosis pathway, i.e. in HepG2 cells treated with Melphalan and in primary hepatocytes irradiated with UV light, only VPA exhibited significant sensitisation.These findings extend the biochemical, pharmacological and toxicological basis for HDI therapy and provide a caveat for clinical use in patients with an accompanying critical inflammatory state in which the CD95 system might be pre-activated.

Calmodulin/CaMKII‐γ mediates prosurvival capability in apicidin‐persistent hepatocellular carcinoma cells via ERK1/2/CREB/c‐fos signaling pathway

“…Deacetylation is mediated by histone deacetylase (HDAC), which catalyzes the removal of acetyl functional group from the N‐terminal tails of histone proteins, resulting in a more compact chromatin structure and represses gene transcription. Previous studies have indicated that the higher expression of HDACs is associated with tumor cell proliferation, differentiation, invasion, and metastasis and is highly correlated to poor prognosis and survival rate 4,5 . HDACs are involved in gene regulations, stress resistance, and tumorigenicity in HCC 6 .…”

“…Apicidin, a novel class of HDAC inhibitor derived from a fungal metabolite, 7 is involved in regulating the HAC process by affecting the balance between histone acetyltransferases and HDACs. Previous studies have reported that apicidin is effective against various cancer cell lines because of its potent antiproliferative property; thus, it is considered a potential anticancer therapeutic agent 4,5 . Moreover, the combination of apicidin with other anticancer drugs, such as doxorubicin, increases the antitumor effects of doxorubicin via induction of apoptosis‐related proteins and cell growth inhibition in HCC 8 …”

Apicidin-Resistant HA22T Hepatocellular Carcinoma Cells strongly activated the Wnt/β-Catenin Signaling Pathway and MMP-2 Expression via the IGF-IR/PI3K/Akt Signaling Pathway Enhancing Cell Metastatic Effect

“…[44][45][46] It has been reported to have a potent broad spectrum of antiproliferative activities against various cancer cell lines. [47][48][49] The combination of apicidin with doxorubicin enhances the antitumor effect of doxorubicin on caspase activation and tumor growth in HCCs, 50) but, the growth-inhibitory concentrations of apicidin in HCCs were higher than MCF-7 breast, AGS gastric and HepG2 liver cancer cell lines. 19,20) Thus, induction of side effects and chemoresistance by apicidin can be expected for HCCs treatment.…”