Abstract
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 (MetAPZ) 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 G, stage of mitosis. An intracellular accumulation of p21WAF1/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.
| Original language | English |
|---|---|
| Pages (from-to) | 124-130 |
| Number of pages | 7 |
| Journal | International Journal of Cancer |
| Volume | 114 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2005 Mar 10 |
| Externally published | Yes |
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Keywords
- Angiogenesis
- Apoptosis
- Endothelial cells
- Tumor immunity
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. / Chun, Eunyoung; Han, Cheol Kyu; Yoon, Jeong Hyeok; Sim, Taebo; Kim, Yoon Keun; Lee, Ki Young.
In: International Journal of Cancer, Vol. 114, No. 1, 10.03.2005, p. 124-130.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model
AU - Chun, Eunyoung
AU - Han, Cheol Kyu
AU - Yoon, Jeong Hyeok
AU - Sim, Taebo
AU - Kim, Yoon Keun
AU - Lee, Ki Young
PY - 2005/3/10
Y1 - 2005/3/10
N2 - 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 (MetAPZ) 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 G, stage of mitosis. An intracellular accumulation of p21WAF1/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.
AB - 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 (MetAPZ) 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 G, stage of mitosis. An intracellular accumulation of p21WAF1/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.
KW - Angiogenesis
KW - Apoptosis
KW - Endothelial cells
KW - Tumor immunity
UR - http://www.scopus.com/inward/record.url?scp=13244265583&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13244265583&partnerID=8YFLogxK
U2 - 10.1002/ijc.20687
DO - 10.1002/ijc.20687
M3 - Article
VL - 114
SP - 124
EP - 130
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 1
ER -