Cytoskeleton-interacting activity of geiparvarin, diethylstilbestrol and conjugates

Geiparvarin, a natural compound isolated from the leaves of Geijera parvifl ora, inhibits the growth of various tumor cell lines with a mode of action which may be attributed to its anti-microtubular activity. Our previous fin dings indicated that gelparvarin is able to inhibit the in vitro polymeriza tion of tubulin and to derange the microtubular network in fibroblasts more effectively in the presence of paclitaxel. To further explore its biologic al activity here we have studied the effects exerted on the other component s of the cytoskeleton by geiparvarin and two derivatives obtained by conjug ating the 3(2H)-furanone ring of geiparvarin with diethylstilbestrol (DES). Firstly, observations by electron microscopy confirmed anti-microtubular p roperties, a near-total absence of microtubules is detected when tubulin is incubated with drugs in the presence of paclitaxel, whereas microtubule fo rmation is not inhibited by drugs when assembly is induced by guanosine 5'- triphosphate (GTP). Immunofluorescence assays demonstrated that geiparvarin and DES act in a vinblastine-like fashion, causing a marked depletion of i ntermediate filaments while the network of microfilaments is not affected. Both the conjugates alter the 'stress fibers' organization of actin and dis rupt the vimentin pattern; generally they derange cytoskeleton more markedl y than the parent compounds. The cell growth inhibiting effects of geiparva rin and derivatives are dose-dependent, they vary according to the cell lin e used, when compounds were administered either alone or simultaneously wit h paclitaxel. Unlike other anti-microtubule agents, they do not exhibit cel l-cycle compartment specificity and do not influence thymidine uptake in th e cell. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.