KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+ATP channel opening in its antiangiogenic effect

Kim, Ki Young; Kim, Sun-Ok; Lim, Hong; Yoo, Sung‐Eun; Hong, Ki Whan

doi:10.1016/s0014-2999(03)01493-6

Cited by 4 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the previous results, glibenclamide reversed the KR-31372-induced suppression of the VEGF 165 -stimulated chemotactic motility of HUVECs (Kim et al, 2003). At that time, they did not identify whether the action site of glibenclamide is on the sarcolemmal K ATP channels or the mitoK ATP channels.…”

Section: Discussionmentioning

confidence: 79%

“…Tamura et al (1998) have emphasized the importance of PTEN in the cell migration, in that overexpression of PTEN dephosphorylates FAK in vivo and in vitro, and reduces its tyrosine phosphorylation and inhibits integrin-mediated cell spreading, whereas antisense PTEN enhanced migration. Most recently, Kim et al (2003) have demonstrated that KR-31372 significantly inhibited the KDR/Flk-1 tyrosine phosphorylation-linked extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and p125 FAK tyrosine phosphorylation, which were inhibited by glibenclamide, a K ATP channel blocker. Considering that KR-31372 significantly suppressed the VEGF-stimulated triad of angiogenesis (DNA synthesis, migration, and MMP-2 release; data not shown) in HUVECs, it is likely predictable that KR-31372 might suppress the tube formation in HUVECs and Matrigel-induced neovascularization in mice via mediation of the mitoK ATP opening, thereby leading to the antiangiogenesis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation

Kim¹,

Shin²,

Sun-Ok³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation

Kim¹,

Shin²,

Sun-Ok³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

View full text Add to dashboard Cite

“…5). Clinical studies have suggested that tumor cell cyclmg may be an important prognostic marker for disease-fi-ee survival in metastatic breast cancer, but that Ki-67 labeling index, tumor microvessel density (MVD) and neovascularization appear to be independently regulated processes (55)(56). To our knowledge, this is the first report of a significant reduction in tumor labeling index produced by a vascular targeting agent.…”

Section: Discussionmentioning

confidence: 99%

“…A closely-related toxin, ricin-A chain (RTA) also generates an apoptotic damage to target cells (49,50), however, Baluna et al (51) suggest that different portions of the RTA molecule may be responsible for generating apoptotic and necrotic effects. VEGF-A has been shown to play a role in tube formation of endothelial cells in vitro (52,53) as well as angiogenesis (54)(55)(56). The effect of VEGFi2i/rGel on tube formation of endothelial cells on matrigel-coated plates was striking in that KDR over-expressing cells but not cells over-expressing the FLT-1 receptor were affected.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

Rosenblum¹

2005

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Infonnatlon Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. and TITLE AND SUBTITLEEvaluation of Novel Agents which Target Neovasculature of Breast Tumors AUTHOR(S)Michael Rosenblum, Ph.D. FUNDING NUMBERSDAMD17-02-1-0457 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)The ABSTRACT (Maximum 200 Words)The unique fusion toxin VEGFiji/rGel can specifically kill both log-phase and confluent vascular endothelial cells expressing the KDR receptor for VEGF (PNAS 99:7866,2002). We have discovered 19 unique genes upregulated{>5 fold) in endothelial cells treated with VEGFi2i/rGel(confirmed by Western and RT-PCR).VEGFi2i/rGel(i.v.) treatment had a dramatic cytotoxic effect in both orthotopic and metastatic human breast tumor models. Against the orthotopic model, tumor growth was signi'ficantly delayed by~50%. In addition, tumors completely regressed in 3/6 (50%) of treated mice. In the metastatic breast model, treatment with VEGFiji/rGel reduced both the number and area of lung foci by 58% and 50% respectively and we demonstrated VEGFi2i/rGel(by IHC) on lung tumor vasculature but not normal vasculature. In addition, the number of blood vessels per mm^ in metastatic foci was 198+ 37 versus 388-1-21 for treated and control respectively. Approximately 62% of metastatic colonies from the VEGF/rGel treated group had <10 vessels/colony compared to 23% in the control group. The fll<-l receptor on blood vessel endothelium was intensely expressed on control tumors, but not expressed on treated tumors. Metastatic foci had a 3 fold lower Ki-67 labeling index compared to control tumors. This suggests that VEGFi2i/rGel has impressive antitumor activity in breast cancer. SUBJECT TERMS Reportable Outcomes 16Conclusions 17 References 18Appendices 22 Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors IntroductionBiological studies examining the development of the vascular tree in normal development and in disease states have identified numerous cytokines and their receptors responsible for triggering and maintaining this process (1-7). Tumor neovascularization is central not only to the growth and development of the primary lesion but appears to be a critical factor in the development and maintenance of metastases (8)(9)(10)(11)(12). Clinical studies in bladder cancer (9) have demonstrated a correlation between micro-vessel density and metastases. In addition, studies of breast cancer metastases by have demonstrated that microvessel coimt in primary tumors appears to be related to the presenc...

show abstract

“…The most studied HIF-regulated pro-angiogenesis factor is probably VEGF, the angiogenesis cytokine that regulates endothelial cell proliferation and blood vessel formation. Both VEGF and its receptors VEGFR1 (FLT-1) and VEGFR2 (KDR/FLK1), which are located principally on the surface of endothelial cells, are upregulated by HIF (123,185). Fibroblast growth factor (FGF) is also regulated by hypoxia and may act synergistically with VEGF to amplify angiogenesis (125).…”

Section: Angiogenic Switchmentioning

confidence: 99%

Involvement of ion channels and transporters in carcinoma angiogenesis and metastasis

Martial

2016

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Angiogenesis is a finely tuned process, which is the result of the equilibrium between pro- and antiangiogenic factors. In solid tumor angiogenesis, the balance is highly in favor of the production of new, but poorly functional blood vessels, initially intended to provide growing tumors with nutrients and oxygen. Among the numerous proteins involved in tumor development, several types of ion channels are overexpressed in tumor cells, as well as in stromal and endothelial cells. Ion channels thus actively participate in the different hallmarks of cancer, especially in tumor angiogenesis and metastasis. Indeed, from their strategic localization in the plasma membrane, ion channels are key operators of cell signaling, as they sense and respond to environmental changes. This review aims to decipher how ion channels of different families are intricately involved in the fundamental angiogenesis and metastasis hallmarks, which lead from a nascent tumor to systemic dissemination. An overview of the possible use of ion channels as therapeutic targets will also be given, showing that ion channel inhibitors or specific antibodies may provide effective tools, in the near future, in the treatment of carcinomas.

show abstract

KR-31372 inhibits KDR/Flk-1 tyrosine phosphorylation via K+ATP channel opening in its antiangiogenic effect

Cited by 4 publications

References 25 publications

Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation

Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

Involvement of ion channels and transporters in carcinoma angiogenesis and metastasis

Contact Info

Product

Resources

About