Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells

Abstract

Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene expression.

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

“…69 Collectively, the present study and results from previous studies suggest that HDACIs like TUB-A potentiate the effects of PdNPs in caspase-3 activation, which is the underlying mechanism of the apoptosis effect. It clearly suggests that both TUB-A and PdNPs induce caspase-3-dependent apoptosis in MDA-MB-231 cells.…”

Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

“…Preliminary studies have been conducted on the combined use of DNMT inhibitors with existing antitumor agents (10)(11)(12). Accordingly, a preliminary experiment was conducted on a combination of a specific antitumor agents, including CPT-11, SN-38 or 5-FU with one of several epigenetic modifiers including DAC in two different human CRC cell lines; HCT116 and HT29 (13). Marked enhancement of the antitumor activities of CPT-11 or SN-38 with DAC was observed in HCT116 cells, but not in HT29 cells.…”

Tricaproin Isolated From Simarouba glauca Inhibits the Growth of Human Colorectal Carcinoma Cell Lines by Targeting Class-1 Histone Deacetylases

“…Activation of caspase-3 and 7 is the functional end point of apoptotic cascade and is an indicator of apoptosis induction in mammalian cells ( Okada et al, 2016 ). The caspase-3/7 fluorescence assay kit was used to measure the caspase activity 4 .…”