A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

Sjin, Robert M. Tjin Tham; Satchi‐Fainaro, Ronit; Birsner, Amy E.; Ramanujam, V. M. Sadagopa; Folkman, Judah; Javaherian, Kashi

doi:10.1158/0008-5472.can-04-1833

Cited by 101 publications

(89 citation statements)

References 35 publications

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“…However, this peptide was treated at the tumor periphery and for only 7 days. In another study (49), a minimum sequence of 27 amino acid synthetic peptide corresponding to the N-terminal zinc-binding domain of endostatin fully mimicked its antitumor activity. However, the peptide was administrated at a higher frequency (twice a day vs. once a day for fulllength endostatin).…”

Section: Minimum Endostatin Sequence Required For Its Biological Actimentioning

confidence: 96%

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Wang

Liu

et al. 2015

Molecular Cancer Therapeutics

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Endostatin is an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although the molecular mechanisms of endostatin have been extensively explored, the intrinsic biochemical characteristics of endostatin are not completely understood. Here, we revealed for the first time that endostatin embedded novel ATPase activity. Moreover, mutagenesis study showed that the ATPase activity of endostatin mutants positively correlated with effects on endothelial cell activities and tumor growth. E-M, an endostatin mutant with higher ATPase activity than that of wild-type (WT) endostatin, significantly increased endostatin-mediated inhibitory effects on endothelial cell proliferation, migration, tube formation, and adhesion. In vivo study showed that E-M displayed enhanced antitumor effects compared with WT. On the other hand, K96A, K96R, and E176A, endostatin mutants with lower ATPase activities than that of WT, showed reduced or comparable effects on targeting both in vitro endothelial cell activities and in vivo tumor angiogenesis and tumor growth. Furthermore, endostatin and its mutants exhibited distinct abilities in regulations of gene expression (Id1, Id3), cell signaling (Erk, p38, and Src phosphorylation), and intracellular ATP levels. Collectively, our study demonstrates that endostatin has novel ATPase activity, which mediates its antiangiogenic and antitumor activities, suggesting that construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs.

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Section: Minimum Endostatin Sequence Required For Its Biological Actimentioning

confidence: 96%

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Wang

Liu

et al. 2015

Molecular Cancer Therapeutics

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“…However, the antiangiogenic activity has been shown to reside in different regions of the molecule by different groups. For instance, a peptide encompassing the secondary heparin-binding site was the minimal active domain in one in vivo study (Olsson et al, 2004) and the N-terminal 29 amino acids critical in another (Tjin Tham Sjin et al, 2005). While both peptides are antiangiogenic, it is not clear whether they function by the same intracellular effector pathways as each other or as parental endostatin.…”

Section: Peptide Fragmentsmentioning

confidence: 99%

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Clamp

Jayson

2005

Br J Cancer

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Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments.

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“…20 Recently, we have shown that an NH 2 -terminal 27-aminoacid synthetic peptide of endostatin, corresponding to the zinc-binding domain, is responsible for its antitumor properties. 21 Gene therapy is a feasible approach to combat cancer, with a sustained systemic therapeutic release of antiangiogenic substances and a highly localized delivery. Sustained elevated blood levels obtained by continuous administration from an implanted pump have been demonstrated to be significantly more effective against tumors in animals than intermittent peak levels from bolus dosing.…”

Section: Introductionmentioning

confidence: 99%

Endostatin therapy reveals a U-shaped curve for antitumor activity

et al. 2006

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Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.

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A 27-Amino-Acid Synthetic Peptide Corresponding to the NH2-Terminal Zinc-Binding Domain of Endostatin Is Responsible for Its Antitumor Activity

Cited by 101 publications

References 35 publications

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Endostatin therapy reveals a U-shaped curve for antitumor activity

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