Psoralidin

The seeds of Psoralea corylifolia.

Psoralidin, a natural furanocoumarin, is isolated from Psoralea corylifolia L. possessing anti-cancer properties. IC50 value: Target: Anticancer natural compound in vitro: PSO dramatically decreased the cell viabilities in dose- and time-dependent manner. Autophagy inhibitor 3-MA blocked the production of LC3-II and reduced the cytotoxicity in response to PSO. Furthermore, PSO increased intracellular ROS level which was correlated to the elevation of LC3-II [1]. Psoralidin at 10 μM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of psoralidin are mediated by ER [2]. Psoralidin enhanced TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2 death receptor and depolarization of mitochondrial membrane potential [3]. Psoralidin inhibited the IR-induced COX-2 expression and PGE(2) production through regulation of PI3K/Akt and NF-κB pathway. Also, psoralidin blocked IR-induced LTB(4) production, and it was due to direct interaction of psoralidin and 5-lipoxygenase activating protein (FLAP) in 5-LOX pathway. IR-induced fibroblast migration was notably attenuated in the presence of psoralidin [4]. in vivo: Moreover, in vivo results from mouse lung indicate that psoralidin suppresses IR-induced expression of pro-inflammatory cytokines (TNF-α, TGF-β, IL-6 and IL-1 α/β) and ICAM-1[4].

References:
[1]. Hao W, et al. Psoralidin induces autophagy through ROS generation which inhibits the proliferation of human lung cancer A549 cells. PeerJ. 2014 Sep 9;2:e555. [2]. Liu X, et al. Psoralidin, a coumestan analogue, as a novel potent estrogen receptor signaling molecule isolated from Psoralea corylifolia. Bioorg Med Chem Lett. 2014 Mar 1;24(5):1403-6. [3]. Bronikowska J, et al. The coumarin psoralidin enhances anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Molecules. 2012 May 29;17(6):6449-64. [4]. Yang HJ, et al. Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation. Biochem Pharmacol. 2011 Sep 1;82(5):524-34.

Antidepressant-like effects of psoralidin isolated from the seeds of Psoralea Corylifolia in the forced swimming test in mice.[Pubmed:18006202]

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):510-9.

The antidepressant-like effects of Psoralidin isolated from the seeds of Psoralea corylifolia were investigated in the forced swimming test (FST) in ICR strain of male mice. Psoralidin significantly decreased immobility time and increased swimming behavior without altering climbing behavior in the mouse FST after oral administration for 1 h or 3 consecutive days. Psoralidin did not affect locomotor activity in the open-field test. After a 3-day treatment, Psoralidin significantly increased 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions, as well as, changed dopamine (DA) levels in striatum in mice exposed to FST. Psoralidin also ameliorated the elevations in serum corticotropin-releasing factor (CRF), adrenal corticotropin-releasing hormone (ACTH) and corticosterone concentrations induced by swimming stress in mice. These results suggested that Psoralidin possessed potent antidepressant-like properties that were mediated via the monoamine neurotransmitter and the hypothalamic-pituitary-adrenal (HPA) axis systems.

Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation.[Pubmed:21669192]

Biochem Pharmacol. 2011 Sep 1;82(5):524-34.

Radiotherapy is the most significant non-surgical cure for the elimination of tumor, however it is restricted by two major problems: radioresistance and normal tissue damage. Efficiency improvement on radiotherapy is demanded to achieve cancer treatment. We focused on radiation-induced normal cell damage, and are concerned about inflammation reported to act as a main limiting factor in the radiotherapy. Psoralidin, a coumestan derivative isolated from the seed of Psoralea corylifolia, has been studied for anti-cancer and anti-bacterial properties. However, little is known regarding its effects on IR-induced pulmonary inflammation. The aim of this study is to investigate mechanisms of IR-induced inflammation and to examine therapeutic mechanisms of Psoralidin in human normal lung fibroblasts and mice. Here, we demonstrated that IR-induced ROS activated cyclooxygenases-2 (COX-2) and 5-lipoxygenase (5-LOX) pathway in HFL-1 and MRC-5 cells. Psoralidin inhibited the IR-induced COX-2 expression and PGE(2) production through regulation of PI3K/Akt and NF-kappaB pathway. Also, Psoralidin blocked IR-induced LTB(4) production, and it was due to direct interaction of Psoralidin and 5-lipoxygenase activating protein (FLAP) in 5-LOX pathway. IR-induced fibroblast migration was notably attenuated in the presence of Psoralidin. Moreover, in vivo results from mouse lung indicate that Psoralidin suppresses IR-induced expression of pro-inflammatory cytokines (TNF-alpha, TGF-beta, IL-6 and IL-1 alpha/beta) and ICAM-1. Taken together, our findings reveal a regulatory mechanism of IR-induced pulmonary inflammation in human normal lung fibroblast and mice, and suggest that Psoralidin may be useful as a potential lead compound for development of a better radiopreventive agent against radiation-induced normal tissue injury.

Psoralidin, a coumestan analogue, as a novel potent estrogen receptor signaling molecule isolated from Psoralea corylifolia.[Pubmed:24507928]

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1403-6.

A novel biological activity of Psoralidin as an agonist for both estrogen receptor (ER)alpha and ERbeta agonist has been demonstrated in our study. Psoralidin has been characterized as a full ER agonist, which activates the classical ER-signaling pathway in both ER-positive human breast and endometrial cell lines as well as non-human cultured cells transiently expressing either ERalpha or ERbeta. The estrogenic activity was determined using the relative expression levels of either reporter or the endogenous genes dependent on the agonist-bound ER to the estrogen response element (ERE). Psoralidin at 10 muM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by Psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of Psoralidin are mediated by ER. Psoralidin was also able to induce the endogenous estrogen-responsive gene, pS2, in human breast cancer cells MCF-7. It was observed that activation of the classical ER-signaling pathway by Psoralidin is mediated via induction of ER conformation by Psoralidin and direct binding of the Psoralidin-ER complex to the EREs present in the promoter region of estrogen-responsive genes, as shown by chromatin immunoprecipitation assay results. Finally, molecular docking of Psoralidin to the ligand binding pocket of the ERalpha showed that Psoralidin is able to mimic the binding interactions of E2, and thus, it could act as an ER agonist in the cellular environment.

Psoralidin induced reactive oxygen species (ROS)-dependent DNA damage and protective autophagy mediated by NOX4 in breast cancer cells.[Pubmed:27387402]

Phytomedicine. 2016 Aug 15;23(9):939-47.

BACKGROUND: Psoralidin (PSO), a natural phenolic coumarin, was reported to have anti-cancer activities. PSO induced reactive oxygen species (ROS) generation in cancer cells. The role of ROS in its anti-cancer effect remains unclear. PURPOSE: This study was designed to investigate the potential roles of ROS in PSO-induced anti-cancer effect in MCF-7 breast cancer cells. METHODS: Effect of PSO on cancer cell proliferation was determined by MTT assay. Comet assay was used to determine DNA damage. Protein expression was detected by Western blotting. Autophagic vacuoles were detected by monodansylcadaverine (MDC) staining. ROS generation was measured by fluorescent probe. NOX4 localization was determined by immunofluorescence staining. RESULTS: PSO treatment caused proliferation inhibition in time- and dose- dependent manners, which was partially reversed by N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI). PSO induced DNA damage and increased protein expression of gamma-H2AX, phosphorylation of ATM, ATR, Chk1, and Chk2. PSO induced autophagy as evidenced by the accumulation of autophagic vacuoles and alterations of autophagic protein expression. PSO-induced cell death was enhanced by autophagy inhibitor chloroquine (CQ). Furthermore, PSO treatment induced ROS formation, which was reversed by NAC or DPI pretreatment. The expression of NOX4 was significantly enhanced by PSO. Both NAC and DPI could reverse PSO-induced DNA damage and autophagic responses. In addition, silencing NOX4 by siRNA inhibited PSO-induced ROS generation, DNA damage, and autophagy. CONCLUSIONS: Taken together, these results showed that PSO induced DNA damage and protective autophagy mediated by ROS generation in a NOX4-dependent manner in MCF-7 cells.

Psoralidin inhibits proliferation and enhances apoptosis of human esophageal carcinoma cells via NF-kappaB and PI3K/Akt signaling pathways.[Pubmed:27446379]

Oncol Lett. 2016 Aug;12(2):971-976.

Esophageal cancer is the most common gastrointestinal cancer. Psoralidin exhibits antioxidant, anti-apoptotic, anti-inflammatory and antitumor effects, which result in the inhibition of cancer formation. The present study aimed to investigate the effect of Psoralidin on esophageal carcinoma proliferation and growth, and to elucidate its underlying mechanism of action. The effect of Psoralidin on cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Using an annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit and 4',6-diamidino-2-phenylindole staining assay, the present study demonstrated that Psoralidin significantly enhanced apoptosis of human esophageal carcinoma Eca9706 cells. In addition, caspase-3 activity was analyzed with a caspase-3 colorimetric assay kit, while nuclear factor (NF)-kappaB activity and protein phosphatidylinositol 3-kinase (PI3K)/Akt expression were measured with an NF-kappaB enzyme-linked immunosorbent assay kit and western blot analysis, respectively. Eca9706 cells were treated with a PI3K agonist in order to investigate the mechanism of action of Psoralidin. It was observed that Psoralidin was able to decrease the proliferation and promote the cellular apoptosis of Eca9706 cells in a dose-dependent manner. Furthermore, Psoralidin was also able to inhibit the caspase-3 activity of Eca9706 cells in a dose-dependent manner. In addition, Psoralidin inhibited NF-kappaB activity and reduced PI3K and Akt protein expression in Eca9706 cells. Notably, the PI3K agonist was able to reverse the effect of Psoralidin on Eca9706 cells. The results of the present study demonstrated that Psoralidin was able to inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells via the NF-kappaB and PI3K/Akt signaling pathways.

Psoralidin inhibits LPS-induced iNOS expression via repressing Syk-mediated activation of PI3K-IKK-IkappaB signaling pathways.[Pubmed:20951127]

Eur J Pharmacol. 2011 Jan 10;650(1):102-9.

Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of Psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, Psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IkappaB kinase (IKK) phosphorylation, IkappaB degradation and nuclear factor kappaB (NF-kappaB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. Exposure to wortmannin abrogated IKK/IkappaB/NF-kappaB-mediated iNOS expression, suggesting activation of such a signal pathway might also be phosphoinositide-3-kinase (PI3K) dependent. By using Src inhibitor PP2, Janus kinase 2 (JAK-2) inhibitor AG490, Bruton's tyrosine kinase (Btk) inhibitor LFM-A13 and spleen tyrosine kinase (Syk) inhibitor piceatannol, the results showed that piceatannol clearly repressed NO production more potently than the other inhibitors. Furthermore, piceatannol significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IkappaB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/Akt-mediated signaling. In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by Psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of Psoralidin via blocking IKK/IkappaB signaling propagation in LPS-stimulated RAW 264.7 macrophages.

The coumarin psoralidin enhances anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).[Pubmed:22643355]

Molecules. 2012 May 29;17(6):6449-64.

Coumarins are a very common type of secondary plant metabolites with a broad spectrum of biological activities. Psoralidin is a naturally occurring furanocoumarin isolated from Psoralea corylifolia possessing anticancer and chemopreventive properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in cancer cells with no toxicity toward normal tissues. Endogenous TRAIL plays an important role in immune surveillance and defence against cancer cells. Coumarins can modulate TRAIL-mediated apoptosis in cancer cells. We examined the cytotoxic and apoptotic activities of Psoralidin in combination with TRAIL on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining and mitochondrial membrane potential was evaluated using DePsipher staining by fluorescence microscopy. Death receptor (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression was analyzed using flow cytometry. Psoralidin enhanced TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2 death receptor and depolarization of mitochondrial membrane potential. Our study indicated that Psoralidin augmented the anticancer effects of TRAIL and confirmed a potential use of coumarins in cancer chemoprevention.

The cytotoxicity of psoralidin from Psoralea corylifolia.[Pubmed:8792669]

Planta Med. 1996 Aug;62(4):353-4.

A cytotoxic coumestan derivative, Psoralidin (1), was isolated from the seed of Psoralea corylifolia. The IC50 values of 1 against SNU-1 and SNU-16 carcinoma cell lines were 53 and 203 micrograms/ml, respectively, indicating cytotoxic activity against stomach carcinoma cell lines.

Psoralidin, isolated from the seed of Psoralea corylifolia, is a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation.Anti-cancer, anti-bacterial, and anti-inflammatory properties. Psoralidin significantly downregulates NOTCH1 signaling. Psoralidin also greatly induces ROS generation.

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