Tumor necrosis factor-alpha (
TNF-alpha) is a proinflammatory
cytokine playing a part in various pathological states. Non-toxic inhibitors of
TNF-alpha release are thought to be promising agents for
cancer prevention. We found that the
acetone fraction of the tobacco leaf surface
lipid containing
glucose esters and
sucrose esters inhibited both
TNF-alpha release from BALB/3T3 and KATO III cells induced by
okadaic acid and
tumor promotion by
okadaic acid on mouse skin initiated with
7,12-dimethylbenz(a)anthracene (DMBA). Next, we investigated the inhibition of
TNF-alpha release with synthetic
disaccharide esters, such as 6,6'-di-O-alkanoyl-alpha, alpha-trehaloses (6,6'-diester-trehaloses), 4,4'-di-O-alkanoyl-alpha, alpha-trehaloses (4,4'-diester-trehaloses) and 6,6'-diamino-6,6'-dideoxy-N,N'-dialkanoyl-alpha, alpha-trehaloses (6,6'-diamide-trehaloses) bearing
fatty acids of various chain lengths, and
n-dodecyl-beta-D-maltoside as a
disaccharide monoester. 6,6'-Diester-trehaloses and 4,4'-diester-trehaloses of C8 to C12
fatty acids, 6,6'-diamide-trehaloses of C8 to C14
fatty acids, and
n-dodecyl-beta-D-maltoside all inhibited
TNF-alpha release in a dose-dependent manner. The IC50 values are 7.4-14.8 microM for 6,6'-diester-trehaloses (C8 to C12), 14.6-21.6 microM 4,4'-diester-trehaloses (C8 to C12), 2.9-15.0 microM for 6,6'-diamide-trehaloses (C8 to C14) and 23 microM for
dodecyl-beta-D-maltoside. Both 6,6'-di-O-octanoyl-alpha, alpha-
trehalose (C8, designated as SS555) and
n-dodecyl-beta-D-maltoside (C12) inhibited
tumor promotion by
okadaic acid on mouse skin initiated with DMBA. Percentages of
tumor-bearing mice in week 15 of
tumor promotion were reduced from 60.0 to 13.3 with SS555, and to 46.7 with
n-dodecyl-beta-D-maltoside. Moreover, SS555 inhibited
TNF-alpha gene expression mediated through inhibition of
AP-1 activation, but not
NF-kappa B activation. This paper reports that diester-trehaloses of C8 to C12
fatty acids and mimics of
disaccharide monoesters such as
n-dodecyl-beta-D-maltoside appear to be potential
cancer-preventive agents of a new type.