Cucurbitacins cytotoxic effects

Widespread reports indicate that, in addition to their anti-inflammatory role, triterpenes have other activities. Triterpenoids have been found to possess cytotoxic, antimicrobial and interesting effects on metabolism. Triterpenoids with antitumour activity include oleanane, lanostane, lupane, friedelane, hopane and quassionoid types. Glycyrrhetinic acid has been described as an antiviral, hypolipidemic and anti-atherosclerotic agent. Cucurbitacins B and E, and oleanolic acid possess a potent protective action on the liver, and ganoderic acid and its derivatives have been shown to be inhibitors of cholesterol biosynthesis. Lanostane derivatives, like suberosol, have also been found to inhibit HIV replication in H9 lymphocytes [1,3]. 

One of the highest priorities in cucurbitacin research has been the exploration of both the cytotoxic and anticancer effects of these compounds. This is due to the fact that they are generally considered to have a high level of toxicity, presumably also against cancer cells. 

Picracin (cucurbitacin Q) and deacetylpicracin (cucurbitacin O) from Picrorhiza scrophulariaeflora, Fig. (13), inhibited phytohemagglutinin-induced T-lymphocyte proliferation in a dose-dependent manner with an IC50 of 1 (iM. This effect cannot be due to the cytotoxicity of the compounds since in specific experiments the authors demonstrated that neither cucurbitacin exhibits toxic effects for IC50 values up to 50 pM. The mechanism of action seems to be an interference with the cytoskeleton and subsequent abrogation of proliferative signal transduction, which in turn inhibits T-lymphocyte proliferation [70]. 

Further fractionation of the active ethanol extract of Desfontainia spinosa based on cytotoxicity has led to the discovery of two novel, cytotoxic glycosides of the parent, 11-deoxocucurbitacin I, named spinoside A (8) and spinoside B (9). The structures of 8 and 9 were established on the basis of extensive analysis of their high field NMR, NMR, high resolution mass spectra (FAB, FD, Cl, El) and chemical interconversions (ref. 57). The novel arabinopyranoside derivatives of 6 were less cytotoxic than the parent compound in the 9PS system. Cucurbitacins although highly cytotoxic have never demonstrated significant anticancer effects in vivo. 

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