JS-K has potent anti-angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo.

Abstract

OBJECTIVES:

Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity.

METHODS:

We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice.

KEY FINDINGS:

JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 microm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 microm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 microm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 microm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells.

CONCLUSIONS:

JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment.

• Authors: Tanyel Kiziltepe, Kenneth C Anderson, Jeffery L Kutok, Lee Jia, Kenneth M Boucher, Joseph E Saavedra, Larry K Keefer, Paul J Shami
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 62 Issue 1 Pg. 145-51 (Jan 2010) ISSN: 2042-7158 [Electronic] England
• PMID: 20723011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Azo Compounds
• O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
• Piperazines

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Aorta, Thoracic (drug effects, metabolism)
• Azo Compounds (administration & dosage, pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chick Embryo
• Endothelial Cells (drug effects, metabolism)
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Multiple Myeloma (blood supply, drug therapy)
• Neoplasm Transplantation
• Neovascularization, Pathologic (drug therapy)
• Piperazines (administration & dosage, pharmacology)
• Time Factors
• Umbilical Veins (cytology, metabolism)