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Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells
C S Navara1, A Benyumov, A Vassilev
1Parker Hughes Cancer Center, Departments of Cell Biology, Oncology, Chemistry and Drug Discovery Program, Parker Hughes Institute, St Paul, MN 55113, USA. cnavara@ih.org
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.
Insights
Organometallic compounds vanadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) show potent anti-cancer effects by disrupting cell division. These vanadocene compounds effectively inhibit cancer cell proliferation and induce mitotic spindle abnormalities, warranting further drug development.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Organometallic compounds are being explored for therapeutic potential.
- Vanadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) are organometallic compounds with unknown biological activity.
- Understanding novel anti-cancer mechanisms is crucial for drug development.
Purpose of the Study:
- To investigate the anti-proliferative effects of VDC and VDacac.
- To elucidate the mechanism of action of VDC and VDacac on cell division.
- To evaluate the potential of vanadocene complexes as anti-cancer agents.
Main Methods:
- Zebrafish embryonic development assays.
- MTT assays for human breast cancer (BT-20) and glioblastoma (U373) cell lines.
- Immunofluorescence microscopy to analyze mitotic spindle formation and gamma-tubulin localization.
- Cell cycle analysis to determine cell cycle arrest points.
Main Results:
- VDC and VDacac inhibited Zebrafish embryonic development at the 8-16 cell stage, causing cell fusion and developmental arrest.
- Both compounds demonstrated concentration-dependent inhibition of human cancer cell proliferation, with VDC and VDacac exhibiting IC50 values in the low to mid-micromolar range.
- Vanadocene treatment resulted in aberrant monopolar mitotic structures, disrupted bipolar spindle formation, and abnormal gamma-tubulin distribution, leading to G2/M cell cycle arrest.
Conclusions:
- VDC and VDacac are potent anti-proliferative agents against human cancer cell lines.
- Vanadocene compounds disrupt cell division by inhibiting bipolar spindle formation, a novel anti-mitotic mechanism.
- These findings support the further development of vanadocene complexes as potential anti-cancer drugs.