Among the 25
bis(cyclopentadienyl)vanadium(IV) and 14
oxovanadium(IV) compounds synthesised and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (
metvan) was identified as the most promising multitargeted anticancer
vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations,
metvan induces apoptosis in human leukaemia cells,
multiple myeloma cells and solid tumour cells derived from
breast cancer,
glioblastoma, ovarian, prostate and
testicular cancer patients. It is highly effective against
cisplatin-resistant
ovarian cancer and
testicular cancer cell lines.
Metvan is much more effective than the standard chemotherapeutic agents
dexamethasone and
vincristine in inducing apoptosis in primary leukaemia cells from patients with acute lymphoblastic leukaemia, acute myeloid leukaemia or chronic acute myeloid leukaemia.
Metvan-induced apoptosis is associated with a loss of mitochondrial transmembrane potential, the generation of
reactive oxygen species and depletion of
glutathione. Treatment of leukaemia cells from acute lymphoblastic leukaemia, acute myeloid leukaemia and chronic acute myeloid leukaemia patients with
metvan inhibits the constitutive expression as well as the gelatinolytic activities of
matrix metalloproteinase-9 and -2. Treatment of human malignant
glioblastoma and
breast cancer cells with
metvan at concentrations > 1 microM is associated with a nearly complete loss of the adhesive, migratory and invasive properties of the treated
cancer cell populations.
Metvan shows favourable pharmacokinetics in mice and does not cause acute or subacute toxicity at the dose levels tested (12.5 - 50 mg/kg). Therapeutic plasma concentrations > or = 5 microM, which are highly cytotoxic against human
cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after intraperitoneal bolus injection of a single 10 mg/kg non-toxic dose of
metvan.
Metvan exhibits significant antitumour activity, delays tumour progression and prolongs survival time in severe combined immunodeficient mouse xenograft models of human malignant
glioblastoma and
breast cancer. The broad spectrum anticancer activity of
metvan together with favourable pharmacodynamic features and lack of toxicity warrants further development of this oxovanadium compound as a new
anticancer agent.
Metvan could represent the first
vanadium complex as an alternative to
platinum-based
chemotherapy.