Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model.
Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR-803, IDR-804, IDR-805 and CKD-732 (designed by structure-based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G1 stage of mitosis. An intracellular accumulation of p21(WAF1/Cip1) protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU-398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers.
Chun
Eunyoung
E
Immune-2 Team, Mogam Biotechnology Research Institute, Yongin-city Kyonggi-do, South Korea.
Han
Cheol Kyu
CK
Yoon
Jeong Hyeok
JH
Sim
Tae Bo
TB
Kim
Yoon-Keun
YK
Lee
Ki-Young
KY
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology; D003510:Cyclohexanes; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014471:Umbilical Veins
D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D003510:Cyclohexanes; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; C496599:IDR-803; C496601:IDR-804; C496602:IDR-805; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; C487952:CKD732; D000077609:O-(Chloroacetylcarbamoyl)fumagillol