Open AccessJS‐K has potent anti‐angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo
Author(s) -
Kiziltepe Tanyel,
Anderson Kenneth C.,
Kutok Jeffery L.,
Jia Lee,
Boucher Kenneth M.,
Saavedra Joseph E.,
Keefer Larry K.,
Shami Paul J.
Publication year - 2010
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1211/jpp.62.01.0017
Subject(s) - angiogenesis , in vivo , in vitro , pharmacology , cancer research , chemistry , biology , medicine , immunology , biochemistry , microbiology and biotechnology
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 μ m 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 μ m , respectively. JS‐K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 μ m . In the chick aortic ring assay using VEGF or FGF‐2 for vessel growth stimulation, 0.5 μ m 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.