Isoginkgetin

Isoginkgetin is a MMP-9 inhibitor, also a Pre-mRNA Splicing Inhibitor with IC 50 of 30 uM. target : MMP-9 [1], Pre-mRNA Splicing [2] IC 50: 30 u M (Pre-mRNA Splicing) In vitro: Isoginkgetin inhibits HT1080 tumor cell invasion substantially. Isoginkgetin is also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Isoginkgetin treatment result in marked decrease in invasion of these cells. isoginkgetin inhibit activities of both Akt and NF-κB. Isoginkgetin markedly decrease MMP-9 expression and invasion through inhibition of this pathway. [1] Splicing inhibition is the mechanistic basis of the anti-tumor activity of isoginkgetin. [2] Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. [3]

References:
[1]. Yoon SO et al. Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. Mol Cancer Ther. 2006 Nov;5(11):2666-75. [2]. O'Brien K et al. The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing. J Biol Chem. 2008 Nov 28;283(48):33147-54. [3]. Liu G et al. Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase. J Endocrinol. 2007 Sep;194(3):569-78.

Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase.[Pubmed:17761896]

J Endocrinol. 2007 Sep;194(3):569-78.

Adiponectin is an anti-diabetic hormone secreted by adipocytes. Circulating adiponectin levels are lower in obese and type II diabetic patients than in healthy people. Weight loss or thiazolidinedione treatment increases plasma adiponectin levels. Animal models and human studies suggest that elevated adiponectin levels increase insulin sensitivity. We screened a library of drug-like compounds and natural products for novel agents enhancing adiponectin production. We identified Isoginkgetin, a compound derived from the leaves of Ginkgo biloba, to up-regulate adiponectin secretion with potency comparable to that of rosiglitazone, a known modulator of adiponectin production. However, unlike rosiglitazone, peroxisome proliferators-activated receptor gamma activity seems not required for the action of Isoginkgetin, and Isoginkgetin has only a slight effect on adipogenesis, which makes it an attractive candidate for anti-diabetic treatment. Further investigation revealed that both Isoginkgetin and rosiglitazone activate AMP-activated protein kinase (AMPK) in adipocytes. Our findings suggest a novel mechanism for the elevation of adiponectin by Isoginkgetin, which is different from that of rosiglitazone. Furthermore, this novel mechanism for adiponectin regulation involving AMPK can potentially facilitate new understanding of metabolic diseases and identification of new targets, as well as agents that increase plasma adiponectin levels.

Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression.[Pubmed:17121913]

Mol Cancer Ther. 2006 Nov;5(11):2666-75.

Matrix metalloproteinase (MMP)-9 plays a key role in tumor invasion. Inhibitors of MMP-9 were screened from Metasequoia glyptostroboides (Dawn redwood) and one potent inhibitor, Isoginkgetin, a biflavonoid, was identified. Noncytotoxic levels of Isoginkgetin decreased MMP-9 production profoundly, but up-regulated the level of tissue inhibitor of metalloproteinase (TIMP)-1, an inhibitor of MMP-9, in HT1080 human fibrosarcoma cells. The major mechanism of Ras-dependent MMP-9 production in HT1080 cells was phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor-kappaB (NF-kappaB) activation. Expression of dominant-active H-Ras and p85 (a subunit of PI3K) increased MMP-9 activity, whereas dominant-negative forms of these molecules decreased the level of MMP-9. H-Ras did not increase MMP-9 in the presence of a PI3K inhibitor, LY294002, and a NF-kappaB inhibitor, SN50. Further studies showed that Isoginkgetin regulated MMP-9 production via PI3K/Akt/NF-kappaB pathway, as evidenced by the findings that Isoginkgetin inhibited activities of both Akt and NF-kappaB. PI3K/Akt is a well-known key pathway for cell invasion, and Isoginkgetin inhibited HT1080 tumor cell invasion substantially. Isoginkgetin was also quite effective in inhibiting the activities of Akt and MMP-9 in MDA-MB-231 breast carcinomas and B16F10 melanoma. Moreover, Isoginkgetin treatment resulted in marked decrease in invasion of these cells. In summary, PI3K/Akt is a major pathway for MMP-9 expression and Isoginkgetin markedly decreased MMP-9 expression and invasion through inhibition of this pathway. This suggests that Isoginkgetin could be a potential candidate as a therapeutic agent against tumor invasion.

The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing.[Pubmed:18826947]

J Biol Chem. 2008 Nov 28;283(48):33147-54.

Membrane-permeable compounds that reversibly inhibit a particular step in gene expression are highly useful tools for cell biological and biochemical/structural studies. In comparison with other gene expression steps where multiple small molecule effectors are available, very few compounds have been described that act as general inhibitors of pre-mRNA splicing. Here we report construction and validation of a set of mammalian cell lines suitable for the identification of small molecule inhibitors of pre-mRNA splicing. Using these cell lines, we identified the natural product Isoginkgetin as a general inhibitor of both the major and minor spliceosomes. Isoginkgetin inhibits splicing both in vivo and in vitro at similar micromolar concentrations. It appears to do so by preventing stable recruitment of the U4/U5/U6 tri-small nuclear ribonucleoprotein, resulting in accumulation of the prespliceosomal A complex. Like two other recently reported general pre-mRNA splicing inhibitors, Isoginkgetin has been previously described as an anti-tumor agent. Our results suggest that splicing inhibition is the mechanistic basis of the anti-tumor activity of Isoginkgetin. Thus, pre-mRNA splicing inhibitors may represent a novel avenue for development of new anti-cancer agents.