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

Abstract

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 micrograms/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 < or = 100 micrograms/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.

Growth Factors in Breast Cancer

“…Multiple growth factors, including FGFs, EGF-related factors, TGFjSs, HGF, and vascular endothelial growth factor (perhaps acting through the FLK oncogene product), are thought to mediate angiogenesis (468,469). Some emerging antiangiogenic therapies target these growth factors with structural antagonists (470), while others, such as AGM1470 (now called TNP 470), do not have fully established mechanisms (471)(472)(473)(474). Chemotherapy seems to synergistically interact with this type of therapy (475).…”

Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis

“…Cinnamamide derivatives display anticancer potential [17, 18], and can be linked with various moieties (such as phenyl, benzyl, or heterocyclic rings) while retaining their biological activity [19–21]. As such, we prepared a series of derivatives of 6-cinnamamido-quinoline-4-carboxamide (CiQ) (Figure 1A, compound 5 ), which were designed as hybrid molecules consisting of a quinoline moiety and a cinnamamide core.…”

Cinnamic acid: A natural product with potential use in cancer intervention

“…Moreover, Wattenberg et al (1980) reported that naturally occurring phenolic derivatives of CINN, i.e., o-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid (caffeic acid), and 4-hydroxy-3-methoxycinnamic acid (ferulic acid), suppressed benzo(a)pyrene-induced neoplasia of the forestomach. Recently, Welch et al (1993) have reported that several cinnanamide compounds isolated from Streptomyces griseoluteus inhibit cancer invasion and metastasis in the melanoma cell lines C8161 and A375 (M).…”