Vanadocenes as potent anti-proliferative agents disrupting mitotic spindleformation in cancer cells

We present experimental data which establish the organometallic compounds v anadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) as poten t anti-proliferative agents. We first examined the effects of VDC and VDaca c on the rapid embryonic cell division and development of Zebrafish. Both c ompounds were capable of causing cell division block at the 8-16 cell stage of embryonic development followed by total cell fusion and developmental a rrest. We next examined the effect of VDC and VDacac on proliferation of hu man breast cancer and glioblastoma cell lines using MTT assays. VDC inhibit ed the proliferation of the breast cancer cell line BT-20 as well as the gl ioblastoma cell line U373 in a concentration-dependent fashion with IC50 va lues of 11.0, 14.9 and 18.6 muM, respectively. VDacac inhibited cellular pr oliferation with IC50 values of 9.1, 26.9 and 35.5 muM, respectively. Where as in vehicle-treated control cancer cells mitotic spindles were organized as a bipolar microtubule array and the DNA was organized on a metaphase pla te, vanadocene-treated cancer cells had aberrant monopolar mitotic structur es where microtubules were detected only on one side of the chromosomes and the chromosomes were arranged in a circular pattern, In contrast to contro l cells which showed a single focus of gamma -tubulin at each pole of the b ipolar mitotic spindle, VDC- or VDacac-treated cells had two foci of gamma -tubulin on the same side of the chromosomes resulting in a broad centrosom e at one pole. All monopolar spindles examined had two foci of gamma -tubul in labeling consistent with a mechanism in which the centrosomes duplicate but do not separate properly to form a bipolar spindle. These results provi de unprecedented evidence that organometallic compounds can block cell divi sion in human cancer cells by disrupting bipolar spindle formation. In acco rdance with these results vanadocene treatment caused an arrest at the G(2) /M phase of the cell cycle. This unique mechanism of anti-mitotic function warrants further development of vanadocene complexes as anti-cancer drugs. [(C) 2001 Lippincott Williams & Wilkins.].