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

Abstract

We present experimental data which establish the organometallic compounds vanadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) as potent anti-proliferative agents. We first examined the effects of VDC and VDacac on the rapid embryonic cell division and development of Zebrafish. Both compounds were capable of causing cell division block at the 8-16 cell stage of embryonic development followed by total cell fusion and developmental arrest. We next examined the effect of VDC and VDacac on proliferation of human breast cancer and glioblastoma cell lines using MTT assays. VDC inhibited the proliferation of the breast cancer cell line BT-20 as well as the glioblastoma cell line U373 in a concentration-dependent fashion with IC50 values of 11.0, 14.9 and 18.6 microM, respectively. VDacac inhibited cellular proliferation with IC50 values of 9.1, 26.9 and 35.5 microM, respectively. Whereas in vehicle-treated control cancer cells mitotic spindles were organized as a bipolar microtubule array and the DNA was organized on a metaphase plate, vanadocene-treated cancer cells had aberrant monopolar mitotic structures where microtubules were detected only on one side of the chromosomes and the chromosomes were arranged in a circular pattern. In contrast to control cells which showed a single focus of gamma-tubulin at each pole of the bipolar mitotic spindle, VDC- or VDacac-treated cells had two foci of gamma-tubulin on the same side of the chromosomes resulting in a broad centrosome at one pole. All monopolar spindles examined had two foci of gamma-tubulin labeling consistent with a mechanism in which the centrosomes duplicate but do not separate properly to form a bipolar spindle. These results provide unprecedented evidence that organometallic compounds can block cell division in human cancer cells by disrupting bipolar spindle formation. In accordance with these results vanadocene treatment caused an arrest at the G2/M phase of the cell cycle. This unique mechanism of anti-mitotic function warrants further development of vanadocene complexes as anti-cancer drugs.

Zebrafish: A new model on the pharmaceutical catwalk

“…In parallel to the increase in p53, we observed very high levels mRNA levels of p21, one of the main downstream effectors of p53. (14) All these data are comparable to the effects of camptothecin in mammalian cell culture. (18) Similar results have been obtained with the small molecule cyclin-dependent kinase inhibitor roscovitine, which likely stabilizes and activates nuclear p53 in tumor cells, possibly via a potent downregulation of Mdm2 transcript and protein levels.…”

“…(14) This compound was microinjected into the cells of embryos in the 2-cell stage and thereafter blocked cell division at the 8-to 16-cell stage of embryonic development followed by cell fusion and developmental arrest. In human cancer cells, proliferation is also inhibited by vanadocene, indicating a similar mode of action.…”

Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapy

“…Vanadocene treatment caused an arrest at the G2/M phase of the cell cycle. This unique mechanism of anti-mitotic function warrants further development of vanadocene complexes as anti-cancer drugs (Navara et al 2001). It has also been shown that vanadocene compounds induced apoptosis in human testicular cancer cell lines (Ghosh et al 2000).…”

Chronic Exposure to Lead Chromate Causes Centrosome Abnormalities and Aneuploidy in Human Lung Cells

“…For example, one study found that vanadium inhibited the separation of the centrosome after duplication causing a monopolar spindle apparatus (21). Three studies on dimethylarsinic all revealed that arsenic induces multiple centrosomes and multipolar spindle formation, which leads to the induction of aneuploidy (22)(23)(24).…”