Do iron chelators increase the antiproliferative effect of trichostatin A through a glucose-regulated protein 78 mediated mechanism?

Abstract

Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA), and iron chelators, including deferoxamine (DFO) and phenanthroline (PHEN), appear to have anticancer effects. We hypothesized that the HDAC inhibitors and iron chelators would be synergistic with their effect on breast cancer cell line MCF7, because the HDAC inhibitors increase glucose-regulated protein 78 (Grp78) and the iron chelators reduce its expression. Although the administration of TSA alone resulted in a dose-related decrease in the cell index, it did not have an antiproliferative effect except the 62.5 and 500 nM of TSA. However, all doses of TSA produced a cytotoxic effect from the initial hours when combined with 150 μM of DFO and 25 μM of PHEN. DFO and PHEN downregulated Grp78, Grp94, and MRP1 expressions and upregulated CHOP and HO-1 expressions. TSA upregulated all the genes in various rates when used alone but resulted in decreased expression levels when combined with DFO and PHEN. Increased HDAC-1 levels in the Grp78 promoter region indicated that DFO and PHEN either promoted binding of HDAC-1 to this region or inhibited its detachment. We determined that the reduction of increased Grp78, Grp94, HO-1, and MRP1 expressions, which appears to inhibit the chemotherapeutic effect of TSA, through the combination with DFO or PHEN will contribute to the anticancer effect.

Trichostatin A induces p53‑dependent endoplasmic reticulum stress in human colon cancer cells

“…However, GRP78 and GRP94 promoter regions were not hyperacetylated following TSA treatment. Previous studies have identified that there are HDAC1 response elements in the promoter region of GRP78 that function as negative regulation factors (17,18). This suggests that TSA may inhibit HDAC1 and induce GRP78 expression.…”

“…Therefore, p53 inactivation may be a driving factor for chemoresistance to TSA in HCT116 cells. Furthermore, a previous study has reported a combined effect of TSA with other factors, including iron chelators (18). Iron chelators promote binding between HDAC-1 and the GRP78 promoter region, which reduces GRP78 expression and promotes the chemotherapeutic effect of TSA.…”

Desferrioxamine biosynthesis: diverse hydroxamate assembly by substrate-tolerant acyl transferase DesC

“…Along with several other bis-and tris-hydroxamates, such as coelichelin (5), erythrochelin (1), vicibactin (3), aerobactin (6) and rhodochelin (4) (figure 1), and other members of the desferrioxamine complex (figure 2), desferrioxamine B (7) plays an important role in microbial iron uptake [8][9][10][11]. Iron is an essential nutrient for most forms of life because it plays a central role in several key metabolic processes.…”

“…The resulting ferric-siderophore complexes are taken up by the microbial cells using ATP-dependent transport mechanisms and the iron is released via reduction or degradation of the ligand [15]. One well-studied example is the model antibiotic-producing actinobacterium Streptomyces coelicolor A3(2), which biosynthesizes and excretes coelichelin (5), desferrioxamine B (7) and desferrioxamine E (8) [11]. Distinct cell surfaceassociated lipoprotein receptor components of ATP-binding cassette (ABC) transporters (CchF and DesE, respectively) are used by S. coelicolor to import the ferricoelichelin and ferrioxamine complexes [16].…”

“…A range of structurally diverse microbial natural products contain one or more hydroxamate functional groups (figure 1), which are employed as metal ion chelators to inhibit or enable important biological processes [1]. Prominent examples include trichostatin A (2), a histone deacetylase (HDAC) inhibitor with anti-cancer activity that is widely used in epigenetics research [2], and desferrioxamine B (7), which is marketed as desferral for the treatment of iron overload and neuroblastoma in humans [3,4]. Trichostatin A blocks histone deacetylation via chelation of its hydroxamate group to the active zinc(II) ion of HDACs [5], whereas desferrioxamine B uses its three hydroxamate groups to sequester ferric iron via formation of a hexadentate complex [6].…”