Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells.
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.
Navara
C S
CS
Parker Hughes Cancer Center, Departments of Cell Biology, Oncology, Chemistry and Drug Discovery Program, Parker Hughes Institute, St Paul, MN 55113, USA. cnavara@ih.org
Benyumov
A
A
Vassilev
A
A
Narla
R K
RK
Ghosh
P
P
Uckun
F M
FM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D018613:Microscopy, Confocal; D008938:Mitosis / Q000187:drug effects; D009423:Nervous System Neoplasms / Q000188:drug therapy / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000648:ultrastructure; D014407:Tumor Cells, Cultured; D017968:Vanadium Compounds / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017968:Vanadium Compounds; C421725:vanadocene acetylacetonate monotriflate; C030754:vanadocene dichloride