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

Christopher S. Navara, Alexey Benyumov, Alexei Vassilev, Rama Krishna Narla, Phalguni Ghosh, Fatih M. Uckun

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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-F 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 μM, respectively. VDacac inhibited cellular proliferation with IC50 values of 9.1, 26.9 and 35.5 μM, 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 γ-tubulin at each pole of the bipolar mitotic spindle, VDC- or VDacac-treated cells had two foci of γ-tubulin on the same side of the chromosomes resulting in a broad centrosome at one pole. All monopolar spindles examined had two foci of γ-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. [

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalAnti-Cancer Drugs
Volume12
Issue number4
DOIs
StatePublished - May 29 2001

Keywords

  • Cell cycle
  • Centrosome
  • Mitotic spindle
  • Vanadium
  • Vanadocene
  • Zebrafish

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