Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

Abstract

Decursinol angelate (DA), an active pyranocoumarin compound from the roots of Angelica gigas, has been reported to possess anti-inflammatory and anti-cancer activities. In a previous study, we demonstrated that prostaglandin E 2 (PGE 2 ) plays a survival role in HL-60 cells by protecting them from the induction of apoptosis via oxidative stress. Flow cytometry and Hoechst staining revealed that PGE 2 suppresses menadione-induced apoptosis, cell shrinkage, and chromatin condensation, by blocking the generation of reactive oxygen species. Treatment of DA was found to reverse the survival effect of PGE 2 as well as restoring the menadione-mediated cleavage of caspase-3, lamin B, and PARP. DA blocked PGE 2 -induced activation of the EP2 receptor signaling pathway, including the activation of PKA and the phosphorylation of CREB. DA also inhibited PGE 2 -induced expression of cyclooxygenase-2 and the activation of the Ras/Raf/ Erk pathway, which activates downstream targets for cell survival. Finally, DA greatly reduced the PGE 2 -induced activation of NF-kB p50 and p65 subunits. These results elucidate a novel mechanism for the regulation of cell survival and apoptosis, and open a gateway for further development and combinatory treatments that can inhibit PGE 2 in cancer cells.

JH‐4 reduces HMGB1‐mediated septic responses and improves survival rate in septic mice

“…In murine models of sepsis, HMGB1 is first detectable in the circulating blood 8 hours after the onset of the disease and subsequently reaches a plateau at 16 to 32 hours after onset. [8][9][10][11] As part of our ongoing research on the identification of novel lead compounds against Hutchinson-Gilford progeria syndrome (HGPS), we recently reported that JH-4, a synthesized decursin derivative, exhibits strong anti-HGPS activity by efficiently blocking progerin-lamin A/C binding. 7 Decursin, a class of linear dihydrocoumarins isolated from the root of Angelica gigas Nakai exhibits a number of physiological activities, including anticancer, antibacterial, neuroprotective, and antioxidant.…”

Lirioresinol B dimethyl ether inhibits NF-κB and COX-2 and activates IκBα expression in CCl4-induced hepatic fibrosis

“…I-κB inhibits NF-κBp65 from nuclear translocation and transcription of inflammatory genes [35]. But in case of liver injury or inflammation, I-κB is phosphorylated and degraded, thus resealing NF-κB where it activates downstream targets to regulate inflammatory gene transcription involved in HSC activation [36]. NF-κB activation has been noted in the HCC model of mice when injected with the carcinogens CCl4 and DEN [35,37].…”

The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis

“…The opening of Cx43-containing HCs has been associated with the suppression of breast cancer proliferation and metastasis [ 197 ]. In several cancers, the opening of HCs results in the release of significant amounts of PGE 2 , which regulates immune cell activation and protects lymphoblastic leukemia cells from other cells [ 198 , 199 ]. These results indicate that the opening of HCs also promotes the survival and metastasis of cancer cells.…”