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U-77,863: a novel cinnanamide isolated from Streptomyces griseoluteus that inhibits cancer invasion and metastasis

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Several cinnamoyl compounds have been shown to have antitumor activities, but not specifically anti-invasive or antimetastatic effects. U-77,863 (o-methyl cinnanamide) was originally isolated from a fermentation beer of Streptomyces griseoluteus and recently synthesized (Harper, DE and Welch DR. Journal of Antibiotics, in press). Based upon some differential activities of cinnanamides, in general, and U-77,863, specifically, we tested the hypothesis that U-77,863 could inhibit invasion and metastasis of human malignant melanoma cell lines C8161 and A375M. Pretreatment of melanoma cells in vitro with nontoxic doses of U-77,863 caused a dose-, and time-dependent, reversible reduction (IC50 = 12.5 µg/ml) of invasion through Matrigel-coated polycarbonate filters in the Membrane Invasion Culture System (MICS). Likewise, lung colonization was significantly (P < 0.05) inhibited when tumor cells were pretreated in vitro with U-77,863 prior to intravenous injection. Structure-activity analysis revealed that the acrylamide side-chain alone and cinnanamide were only slightly less potent than U-77,863, whereas cinnamic acid analogs did not inhibit tumor cell invasion at doses ≤100µg/ml. U-77,863 inhibits invasion and metastasis without decreasing growth rates or clonogenic potential. Adhesion to endothelial monolayers or extracellular matrices (Matrigel) is not affected by exposure to U-77,863. U-77,863 presumably inhibits metastasis by inhibiting tumor cell extravasation (invasion). U-77,863 is a lead compound for developing a novel class of anti-invasive/anti-metastatic drugs.

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  1. Danny R. Welch

    Present address: Division of Experimental Pathology, Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University College of Medicine, 500 University Drive, 17033, Hershey, PA, USA

Authors and Affiliations

  1. Division of Experimental Pathology, Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA

    Danny R. Welch

  2. Cancer Research, Upjohn Research Laboratories, The Upjohn Company, Kalamazoo, MI

    Danny R. Welch & Donald E. Harperf

  3. Medicinal Chemistry Research, Upjohn Research Laboratories, The Upjohn Company, Kalamazoo, MI

    Donald E. Harperf

  4. Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA

    Karin H. Yohem

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  1. Danny R. Welch
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  3. Karin H. Yohem
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Welch, D.R., Harperf, D.E. & Yohem, K.H. U-77,863: a novel cinnanamide isolated from Streptomyces griseoluteus that inhibits cancer invasion and metastasis. Clin Exp Metast 11, 201–212 (1993). https://doi.org/10.1007/BF00114978

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