Methods of modulating angiogenesis and cancer cell proliferation
An angiogenesis, cancer technology, applied in the field of regulation of angiogenesis and cancer cell proliferation, can solve problems such as 20-HETE without evidence
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Embodiment 1
[0075] Regulate skeletal muscle angiogenesis through 20-HETE
[0076]This example demonstrates that 20-hydroxyeicosatetraenoic acid (20-HETE) is important for angiogenesis induced by electrical stimulation in skeletal muscle. Stimulate the anterior tibial muscle and extensor finger longus of the rat for 7 days. Electrical stimulation significantly increased the formation of 20-HETE and angiogenesis in the muscle, which was modified by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016) or 1-aminobenzotriazole ( ABT) chronic treatment is blocked. Chronic treatment with HET0016 or ABT did not block the increase in VEGF protein expression in both muscles. To analyze the effect of VEGF on the formation of 20-HETE, other rats were treated with VEGF neutralizing antibody (VEGF Ab). VEGF Ab blocks stimulation-induced formation of 20-HETE. These results prove that 20-HETE is related to the downstream signaling pathway of angiogenesis (downstream of VEGF).
[0077] Materials and M...
Embodiment 2
[0099] Regulation of growth factor-induced angiogenesis in rat cornea by 20-HETE
[0100] CYP4A enzyme metabolizes arachidonic acid to 20-HETE. In this example, we confirmed that 20-HETE is mitogenic in vitro in endothelial cells in vitro and angiogenic in vivo. We also confirmed that the highly selective CYP4A enzyme inhibitor HET0016 blocks the mitogenic activity of VEGF in endothelial cells. DDMS is another selective inhibitor of CYP4A. We confirmed that HET0016 and DDMS inhibit the angiogenic response of VEGF in vivo. We also confirmed that HET0016 blocks the angiogenic response of bFGF and EGF. We also confirmed that HET0016 reduces angiogenesis induced by U251, a human glioblastoma cell line.
[0101] Materials and Methods
[0102] Reagents:
[0103] As described by Miyata N et al., (Br J Pharmacol 2001, 133:325-9) and Sato M et al., (BioorgMed Chem Lett 2001, 11:2993-5) (the full text is incorporated as a reference), HET0016[N-hydroxy-N '-(4-butyl-2methylphenyl)formamidin...
Embodiment 3
[0158] HET0016 inhibits cell proliferation in human glioma cancer cells
[0159] This example shows that 20-HETE is important for the growth of human cancer cells. 1 μm 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid, a stable 20-HETE agonist, increases the proliferation of human glioma U251 cells by about 20%. Dose-response studies have shown that treatment with 10μM HET0016 for 48 hours inhibits approximately 60% of U251 cell proliferation, while [ 3 H] Thymidine intake is reduced by 65%. Dibromododecenyl methanesulfonimide (DDMS, also known as N-methanesulfonyl-12,12-dibromododecyl-11-enamide), a CYP4A inhibitor with a different structure Blocks about 60% of cell proliferation. Both DDMS and HET0016 have no effect on the basic growth of normal human vascular endothelial cells or keratinocytes. Flow cytometry studies confirmed that HET0016 arrested the cell cycle at G 0 / G 1 To specifically inhibit the proliferation of human U251 cancer cells. The addition of 20-HETE agonist (1 μM) re...
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