Angelicin

J Surg Res. 2013 Nov;185(1):300-9.

Angelicin regulates LPS-induced inflammation via inhibiting MAPK/NF-κB pathways.[Pubmed: 23816246]

Angelicin is a furocoumarin found in Psoralea corylifolia L. fruit. The purpose of this study was to investigate the protective ability of Angelicin against inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and LPS-induced in vivo acute lung injury model.
METHODS AND RESULTS:
The concentrations of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 in the culture supernatants of RAW 264.7 cells were determined 24 h after LPS administration. ALI was induced by intratracheal instillation of LPS. Six hours after LPS inhalation, bronchoalveolar lavage fluid and lung tissue samples were obtained for enzyme-linked immunosorbent assay, histologic, and Western blotting analyses. The results showed that pretreatment with Angelicin markedly downregulated TNF-α and IL-6 levels in vitro and in vivo, and significantly decreased the amount of inflammatory cells, lung wet-to-dry weight ratio, and myeloperoxidase activity in LPS-induced ALI mice. Furthermore, Western blotting analysis results demonstrated that Angelicin blocked the phosphorylation of IκBα, NF-κBp65, p38 MAPK, and JNK in LPS-induced ALI.
CONCLUSIONS:
These results suggest that Angelicin was potentially advantageous to prevent inflammatory diseases by inhibiting NF-κB and MAPK pathways. Our data indicated that Angelicin might be a potential new agent for prevention of inflammatory reactions and diseases in the clinic.

J. Med. Chem., 2010, 53(4):1519-33.

Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives.[Pubmed: 20092255 ]

METHODS AND RESULTS:
By using a cell-based high throughput screening campaign, a novel Angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the Angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4).
CONCLUSIONS:
Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Eur J Haematol. 2003 Sep;71(3):189-95.

Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin.[Pubmed: 12930320]

The aim of the present study was to determine whether Angelicin is able to increase the expression of gamma-globin genes in human erythroid cells. Angelicin is structurally related to psoralens, a well-known chemical class of photosensitizers used for their antiproliferative activity in treatment of different skin diseases (i.e., psoriasis and vitiligo).
METHODS AND RESULTS:
To verify the activity of Angelicin, we employed two experimental cell systems, the human leukemic K562 cell line and the two-phase liquid culture of human erythroid progenitors isolated from normal donors. The results of our investigation suggest that Angelicin, compared with cytosine arabinoside, mithramycin and cisplatin, is a powerful inducer of erythroid differentiation and gamma-globin mRNA accumulation of human leukemia K562 cells. In addition, when normal human erythroid precursors were cultured in the presence of Angelicin, increases of gamma-globin mRNA accumulation and fetal hemoglobin (HbF) production, even higher than those obtained using hydroxyurea, were detected.
CONCLUSIONS:
These results could have practical relevance, as pharmacologically-mediated regulation of the expression of human gamma-globin genes, leading to HbF induction, is considered a potential therapeutic approach in hematological disorders, including beta-thalassemia and sickle cell anemia.

Antiviral Res. 2013 Oct;100(1):75-83.

Antiviral activity of angelicin against gammaherpesviruses.[Pubmed: 23892155]

Human gammaherpesviruses including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are important pathogens as they persist in the host and cause various malignancies. However, few antiviral drugs are available to efficiently control gammaherpesvirus replication.
METHODS AND RESULTS:
Here we identified the antiviral activity of Angelicin against murine gammaherpesvirus 68 (MHV-68), genetically and biologically related to human gammaherpesviruses. Angelicin, a furocoumarin naturally occurring tricyclic aromatic compound, efficiently inhibited lytic replication of MHV-68 in a dose-dependent manner following the virus entry. The IC50 of Angelicin antiviral activity was estimated to be 28.95μM, while the CC50 of Angelicin was higher than 2600μM. Furthermore, incubation with Angelicin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced lytic replication of human gammaherpresviruses in both EBV- and KSHV-infected cells.
CONCLUSIONS:
Taken together, these results suggest that MHV-68 can be a useful tool to screen novel antiviral agents against human gammaherepsviruses and that Angelicin may provide a lead structure for the development of antiviral drug against gammaherpesviruses.

Mol Cell Biochem. 2012 Oct;369(1-2):95-104.

Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells.[Pubmed: 22766766]

Angelicin is structurally related to psoralens, a well-known chemical class of photosensitizers used for its antiproliferative activity in treatment of different skin diseases. To verify the activity of Angelicin, we employed human SH-SY5Y neuroblastoma cells to investigate its cytotoxicity, although its mechanism of action has not yet been fully elucidated.
METHODS AND RESULTS:
Here, we examined the cellular cytotoxicity of Angelicin by cell viability assay, DNA fragmentation by DNA ladder assay, and activation of caspases and Bcl-2 family proteins by western blot analyses. The results of our investigation suggest that Angelicin increased cellular cytotoxicity in a dose- and time-dependent manner with IC(50) of 49.56 μM at 48 h of incubation. In addition, Angelicin dose-dependently downregulated the expression of anti-apoptotic proteins including Bcl-2, Bcl-xL, and Mcl-1 suggesting the involvement of the intrinsic mitochondria-mediated apoptotic pathway which did not participate in Fas/FasL-induced caspase-8-mediated extrinsic, MAP kinases, and PI3K/AKT/GSK-3β pathway. Furthermore, we clarified the dose-dependent upregulation of caspase-9 and caspase-3 which indicated that Angelicin-induced apoptosis is mediated primarily through the intrinsic caspase-mediated pathway. In particular, the caspase-3 inhibitor, DEVD-fmk, induced a reduction in Angelicin-induced cytotoxicity which confirmed that the intrinsic caspase-dependent pathway during this apoptosis which did not prevent cytotoxicity using MAP kinases and GSK-3 inhibitor.
CONCLUSIONS:
Taken together, our data shows that Angelicin is an effective apoptosis-inducing natural compound of human SH-SY5Y neuroblastoma cells which suggests that this compound may have a role in future therapies for human neuroblastoma cancer.