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| ■ Oncology |
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Anti-angiogenic protein, LK8
 Angiogenesis is the formation of new capillaries from the preexisting blood vessels. Substantial evidence has now established that tumor growth and metastasis are angiogenesis-dependent. Neovascularization promotes tumor growth, whereas angiogenesis inhibition prevents them. Consequently, anti-angiogenesis therapy is an attractive and promising future treatment for cancer.
We have previously characterized and produced a recombinant protein, Greenstatin, derived from human
Apolipoprotein (a) and consisting of tandem-repeated kringle domains that closely resemble plasminogen kringles.
Although the physiological and biochemical role(s) of the apo(a) kringle domains are not clearly understood yet,
our recent data have demonstrated that recombinant human apolipoprotein(a) kringle V, termed rhLK8, is a potent
inhibitor of angiogenesis both in vitro and in vivo.
 rhLK8 was expressed
as a secreted soluble protein in Pichia pastoris as well as in Saccharomyces cerevisiae and a
large scale production system was successfully established. rhLK8 inhibits endothelial cell migration in
vitro in a dose-dependent manner. This function is associated with the down-regulation of the activation of
focal adhesion kinase and the inhibition of the consequent formation of actin stress fibers/focal adhesions.
rhLK8 also inhibits new capillary formation in vivo, as assessed by the chick chorioallantoic membrane
assay and a Matrigel plug assay.
Moreover, systemic treatment with rhLK8 significantly suppresses the in vivo growth of human lung (A549),
human prostate (PC-3) and human colorectal (LS174T) cancer cells in nude mice. The treated tumors show reduced
micro vessel density, lower expression of vascular endothelial growth factor and increased tumor cell apoptosis,
whereas proliferation was not affected. These observations suggest that rhLK8 suppresses tumor growth by
interfering with tumor angiogenesis. In addition, rhLK8 can also inhibit the experimental pulmonary and liver
metastasis of B16F10 melanoma cells and CT26 colorectal cancer cells, respectively. Currently, both the clinical
efficacies and the process development of rhLK8 are under investigation.
Publications
Kim, J. S., Yu, H. K., Ahn, J. H., Lee, H. J., Hong, S. W., Jung, K. H., Chang, S. I., Hong, Y. K., Joe, Y. A.,
Byun, S. M., Lee, S. K., Chung, S. I., and Yoon, Y. (2004). Human apolipoprotein(a) kringle V inhibits
angiogenesis in vitro and in vivo by interfering with the activation of focal adhesion kinases. Biochem
Biophys Res Commun 313, 534-540
[PubMed Citation]
Ahn, J. H., Kim, J. S., Yu, H. K., Lee, H. J., and Yoon, Y. (2004). A truncated kringle domain of human
apolipoprotein(a) inhibits the activation of extracellular signal-regulated kinase 1 and 2 through a tyrosine
phosphatase-dependent pathway. J Biol Chem 279, 21808-21814
[PubMed Citation]
Kim, J. S., Chang, J. H., Yu, H. K., Ahn, J. H., Yum, J. S., Lee, S. K., Jung, K. H., Park, D. H., Yoon, Y.,
Byun, S. M., and Chung, S. I. (2003). Inhibition of angiogenesis and angiogenesis-dependent tumor growth by the
cryptic kringle fragments of human apolipoprotein(a). J Biol Chem 278, 29000-29008
[PubMed Citation] |
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