Cdc25A-inhibitory properties and antineoplastic activity of bisperoxovanadium analogues.
Bisperoxovanadium (bpV) compounds are irreversible protein tyrosine phosphatase (PTP) inhibitors with a spectrum of activity distinct from that of vanadium salts. We studied the efficacy of a panel of bpVs as antineoplastic agents in vitro and in vivo with a view to investigating phosphatases as potential antineoplastic targets. The Cdc25A dual-specificity phosphatase is an oncoprotein required for progression through G(1)-S. It cooperates with oncogenic Ras to transform cells and is overexpressed in several cancers. Cdc25A is therefore an attractive candidate phosphatase target for the antineoplastic activity of bpV compounds. Cytotoxicity was examined in 28 cancer cell lines and in vivo efficacy was examined in a DA3 murine mammary carcinoma model. In vitro phosphatase assays were used to directly measure phosphatase inhibition, comparing Cdc25A to hVH2/DSP4, leukocyte antigen related/receptor type PTPF catalytic domain (LAR), Yersinia pestis phosphatase (YOPH), and T-cell PTPase/non-receptor type PTP2 (TCPTP). CDK2 activity and Rb phosphorylation were examined by immunocomplex kinase assays and Western blot. Cdc25A is at least 20-fold more sensitive to bpV inhibition than hVH2/DSP4, and 3- to 10- fold more sensitive than TCPTP and LAR. bpV inhibition of Cdc25A in cells leads to CDK2 inactivation and hypophosphorylation Rb, resulting in G1-S arrest and induction of p53-independent apoptosis. The most cytotoxic analogue, bpV[4,7-dimethyl-1,10-phenanthroline-bisperoxo-oxo-vanadium (Me2Phen)], shows submicromolar IC50s against a panel of cell lines and inhibited tumor growth by 80% in mice. These results demonstrate that bpVs may have significant antineoplastic activity. In addition, they are in vitro and in vivo inhibitors of phosphatases including Cdc25A, suggesting that phosphatases may be appropriate targets for novel antineoplastic agents and that further development of these agents, targeting them to specific phosphatases such as CDC25A, may lead to novel agents with enhanced antineoplastic activity.
Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, Montreal, Quebec, Canada.
P James
PJ
Scrivens
Moulay A
MA
Alaoui-Jamali
Giuseppe
G
Giannini
Taiqi
T
Wang
Martin
M
Loignon
Gerald
G
Batist
Victor A
VA
Sandor
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016196:S Phase; D017968:Vanadium Compounds / Q000627:therapeutic use*; D020687:cdc25 Phosphatases / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D005982:Glutathione Transferase; D010744:Phosphoric Monoester Hydrolases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases