Radicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis

doi:10.1016/0014-2999(93)90206-W

European Journal of Pharmacology

Volume 241, Issues 2–3, 14 September 1993, Pages 221-227

https://doi.org/10.1016/0014-2999(93)90206-W Get rights and content

Abstract

Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficaciuos for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D₃ analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, radicicol (syn. monorden; 5-chloro-6-(7,8-epoxy-10-hydoxy-2-oxo-3,5-undecadi enyl)-β-resorcylic acid μ-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, The ID₅₀ value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy.

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HSP90 inhibition by hebimycin A decreased IKK and NFkB activation, reducing the expression of IL-8 and COX-2 [112]. Radicicol is a fungal metabolite with fungistatic properties originally identified in Monosporium bonorden [113], that binds to HSP90 N-terminal domain and impairs the growth of several tumor cell lines [114,115]. Radicicol has a chemical instability hindering its efficacy in animal models.
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This claim can be endorsed by the fact that radicicol, in addition to inhibition of cancer cells proliferation (73), has also been shown to quench proliferation of activated inflammatory leukocytes and endothelial cells, thereby reducing inflammatory responses in atherosclerosis (74) and experimental pneumonia (75). Radicicol has been also proposed as a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy (76). Importantly, we have also established that treatment with PD0332991 that inhibits the growth of solid tumors (59, 77) can also stimulate elastogenesis in cultures of normal and CS fibroblasts after Rb phosphorylation on Thr-821.
The mechanism that leads to the inverse relationship between heightened cellular proliferation and the cessation of elastic fibers production, observed during formation of the arterial occlusions and dermal scars, is not fully understood. Because the retinoblastoma protein (Rb), responsible for cell cycle initiation, has also been implicated in insulin-like growth factor-I-mediated signaling stimulating elastin gene activation, we explored whether differential phosphorylation of Rb by various cyclin·cyclin-dependent kinase complexes would be responsible for promoting either elastogenic or pro-proliferative signals. We first tested cultures of dermal fibroblasts derived from Costello syndrome patients, in which heightened proliferation driven by mutated oncogenic H-Ras coincides with inhibition of elastogenesis. We found that Costello syndrome fibroblasts display elevated level of Rb phosphorylation on serine 780 (Ser(P)-780-Rb) and that pharmacological inhibition of Ras with radicicol, Mek/Erk with PD98059, or cyclin-dependent kinase 4 with PD0332991 not only leads to down-regulation of Ser(P)-780-Rb levels but also enhances Rb phosphorylation on threonine-821 (Thr(P)-821-Rb), which coincides with the recovery of elastin production. Then we demonstrated that treatment of normal skin fibroblasts with the pro-proliferative PDGF BB also up-regulates Ser(P)-780-Rb levels, but treatment with the pro-elastogenic insulin-like growth factor-I activates cyclinE-cdk2 complex to phosphorylate Rb on Thr-821. Importantly, we have established that elevation of Thr(P)-821-Rb promotes Rb binding to the Sp1 transcription factor and that successive binding of the Rb-Sp1 complex to the retinoblastoma control element within the elastin gene promoter stimulates tropoelastin transcription. In summary, we provide novel insight into the role of Rb in mediating the inverse relationship between elastogenesis and cellular proliferation.
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Cochlioquinone A1 (CoA1) was newly isolated from the culture extract of Bipolaris zeicola as a potent anti-angiogenic agent. CoA1 inhibited in vitro angiogenesis of bovine aortic endothelial cells (BAECs) such as bFGF-induced tube formation and invasion at the concentration (1 μg/mL) without cytotoxicity. Notably, CoA1 exhibited more potent inhibition activity for the growth of BAECs than that of normal and cancer cell lines investigated in this study. These results demonstrate that CoA1 is a new anti-angiogenic agent and can be developed as a new therapeutic agent for angiogenesis-related diseases.
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Radicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis

Abstract

Adv. Cancer Res.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Tetrahedron Lett.

Tetrahedron Lett.

Cancer Lett.

Cancer Lett.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Medroxyprogesterone acetate, an anti-cancer and anti-angiogenic steroid, inhibits the plasminogen activator in bovine endothelial cells

Int. J. Cancer

Angiogenesis and rheumatoid arthritis: pathogenic and therapeutic implications

Ann. Rheum. Dis.

A new antifungal substance of fungal origin

Nature

Angiogenic and angiostatic drugs: reshaping biotech's future

Biotechnology

Angiogenic factors

Science

Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth

Nature

New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein

Cancer Res.

Anti-angiogenic effect of 15-deoxyspergualin in angiogenesis model system involving human microvascular endothelial cells

Cancer J.