Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells

Abstract

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 PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or 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 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.

Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

“…The treatment of MSC-TRAIL did not have an effect toward an increase in GADD45A expression in the CD133+ CSC sample corresponding to a report that showed low expression of GADD45A in NSCLC tissue samples [133]. However, upregulating the GADD45A gene using histone deacetylase (HDAC) inhibitor [134] may enhance the effect of TRAIL and MSC-TRAIL in NSCLC through negative regulation in NFKB1 expression and the inhibition of CSCs [135,136]. Our findings also indicated that the treatment of MSC-TRAIL downregulated the expression of the HRK gene in the CD133+ CSCs.…”

Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B More Efficiently Than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors

“…Enhanced expression of death receptors by numerous natural and chemical agents overcame the resistance of cancer cells to TRAIL [13,15]. Upregulation of death receptors by doxorubicin [24,31], bortezomib [28,32,33] and panobinostat [34] was observed in different types of cancer cells. However, the effect of anticancer drugs on the expression of the decoy receptors DcR1 and DcR2 was poorly studied, although the inhibitory potential of decoy receptors for antitumor activity of TRAIL has been established in many studies [35][36][37][38][39].…”

“…Panobinostat (LBH589) is a histone deacetylase (HDAC) inhibitor, which inhibits all enzymes of the HDAC I, II and IV families in vitro and has strong antitumor activity [20]. The potentiation of apoptotic TRAIL signaling by these agents has been demonstrated in vitro and in vivo in various types of tumors [21][22][23][24].…”

Analysis of Gene Expression of miRNA-106b-5p and TRAIL in the Apoptosis Pathway in Gastric Cancer

“…TRAIL is a pro-apoptotic protein that starts the apoptosis process by binding to its death receptors DR4 and DR5, targeting tumor cells without attacking healthy cells [35][36][37]. For this reason, TRAIL has been considered a promising cancer therapy [16]; however, some studies have shown that gastric cancer cells are resistant to this apoptosis pathway [13,17,18,38].…”