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Bis(4,7-dimethyl-1,10-phenanthroline) Sulfatooxovanadium(IV) as a Novel Antileukemic Agent with Matrix Metalloproteinase Inhibitory Activity

Parker Hughes Cancer Center, Drug Discovery Program [R. K. N., Y. D., D. K., F. M. U.], and Departments of Experimental Oncology [R. K. N., D. K., F. M. U.] and Chemistry [Y. D.], Parker Hughes Institute, St. Paul, Minnesota 55113

We have examined the in vitro anticancer activity of METVAN [bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(IV); VO(SO₄)(Me₂-Phen)₂] against acute lymphoblastic leukemia (ALL; NALM-6 and MOLT-3), acute myeloid leukemia (AML; HL-60), Hodgkin’s disease (HS445), and multiple myeloma (ARH-77, U266BL, and HS-SULTAN) cell lines as well as primary leukemic cells from patients with ALL, AML, and chronic acute myeloid leukemia (CML). METVAN induced apoptosis in NALM-6, MOLT-3, and HL-60 cells in a concentration-dependent fashion with EC₅₀ values of 0.19 ± 0.03 µM, 0.19 ± 0.01 µM, and 1.1 ± 0.2 µM, respectively. METVAN induced apoptosis at low micromolar concentrations in primary leukemic cells from patients with ALL, AML, and CML. METVAN inhibited the constitutive expression of matrix metalloproteinase (MMP)-9 protein and its gelatinolytic activity in HL-60 cells and MMP-2 as well as MMP-9 gelatinolytic activities in leukemic cells from ALL, AML, and CML patients. Furthermore, METVAN inhibited the leukemic cell adhesion to the extracellular matrix proteins laminin, type IV collagen, vitronectin, and fibronectin and the invasion through Matrigel matrix. Further preclinical development of METVAN may provide the basis for the development of more effective chemotherapy programs.

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