%0 Journal Article
%T Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells
%A Baojie Zhang
%A Bin Liu
%A Deng Chen
%A Hidde J. Haisma
%A Rita Setroikromo
%A Wim J. Quax
%J Archive of "Cancers".
%D 2019
%R 10.3390/cancers11050645
%X Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi¡¯s), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi¡¯s, however, show considerable toxicity constraining clinical use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi¡¯s. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi¡¯s on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or {"type":"entrez-protein","attrs":{"text":"PCI34051","term_id":"1247373256"}}PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or {"type":"entrez-protein","attrs":{"text":"PCI34051","term_id":"1247373256"}}PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We observed that RGFP966 and {"type":"entrez-protein","attrs":{"text":"PCI34051","term_id":"1247373256"}}PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models
%K "entrez-protein"
%K "attrs":{"text":"PCI34051"
%K "term_id":"1247373256"}}PCI34051
%K DLD-1
%K WiDr
%K spheroid
%K death receptor
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562715/