Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Jones, Philip H.; Christodoulos, K; Dobbs, Nicola; Thavasu, Parames; Balkwill, Frances R.; Blann, Andrew D.; Caine, Graham J.; Kumar, Shant; Kakkar, Ajay; Gompertz, N R; Talbot, Denis; Ganesan, Trivadi S.; Harris, Adrian L.

doi:10.1038/sj.bjc.6601897

Cited by 34 publications

(20 citation statements)

References 28 publications

(31 reference statements)

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“…The catalytic domain of human TACE was expressed and purified by using reported protocols (23). Fluoregenic peptide QF-45 [Mca-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-SerSer-Ser-Arg-Lys(Dnp)-NH 2 ] was synthesized at the Weizmann Institute core facilities.…”

Section: Methodsmentioning

confidence: 99%

Key feature of the catalytic cycle of TNF-α converting enzyme involves communication between distal protein sites and the enzyme catalytic core

Solomon

Akabayov

Frenkel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Despite their key roles in many normal and pathological processes, the molecular details by which zinc-dependent proteases hydrolyze their physiological substrates remain elusive. Advanced theoretical analyses have suggested reaction models for which there is limited and controversial experimental evidence. Here we report the structure, chemistry and lifetime of transient metal-protein reaction intermediates evolving during the substrate turnover reaction of a metalloproteinase, the tumor necrosis factor-␣ converting enzyme (TACE). TACE controls multiple signal transduction pathways through the proteolytic release of the extracellular domain of a host of membrane-bound factors and receptors. Using stopped-flow x-ray spectroscopy methods together with transient kinetic analyses, we demonstrate that TACE's catalytic zinc ion undergoes dynamic charge transitions before substrate binding to the metal ion. This indicates previously undescribed communication pathways taking place between distal protein sites and the enzyme catalytic core. The observed charge transitions are synchronized with distinct phases in the reaction kinetics and changes in metal coordination chemistry mediated by the binding of the peptide substrate to the catalytic metal ion and product release. Here we report key local charge transitions critical for proteolysis as well as long sought evidence for the proposed reaction model of peptide hydrolysis. This study provides a general approach for gaining critical insights into the molecular basis of substrate recognition and turnover by zinc metalloproteinases that may be used for drug design.dynamics ͉ matrix metalloproteinases ͉ proteolysis ͉ x-ray absorption ͉ stopped flow Z inc-dependent metalloproteinases comprise a large superfamily of enzymes possessing key biological roles. These enzymes use zinc (Fig. 1a) to catalyze the hydrolysis of peptide bonds in a wide variety of substrates in both normal and pathological processes (1, 2). Over the last five decades, substantial efforts have been aimed at understanding the molecular basis by which the catalytic zinc machinery executes such enzymatic reactions (3, 4). Protein crystallography, proteomic, and theoretical studies have been instrumental in proposing reaction mechanisms (3,5,6). However, the molecular details that link the catalytic chemistry to key kinetic, electronic, and structural events have remained elusive because of the difficulties associated with probing time-dependent structure-function aspects of such reactions in the presence of peptide substrates.Here we used a strategy based on dynamic structural spectroscopy to elucidate in detail the molecular mechanisms at work during substrate turnover by TACE. TACE is a disintegrin and metalloproteinase family member (also known as ADAM 17) with key roles in the regulation of the proteolytic release of cytokines, chemokines, growth factors, and receptors from cellular membranes (a process known as ectodomain shedding) (7). We have used stopped-flow freeze-quench x-ray absorption spectros...

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Section: Methodsmentioning

confidence: 99%

Key feature of the catalytic cycle of TNF-α converting enzyme involves communication between distal protein sites and the enzyme catalytic core

Solomon

Akabayov

Frenkel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…A combination therapy of an ACEI, a matrix metalloprotease inhibitor and a low molecular-weight heparin was tested in 50 patients with various advanced malignancies including lung cancer and showed some anticancer activity (Jones et al 2004). Uemura et al (2008) proposed activity of ARB in prostate cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy

Wilop

Hobe

Crysandt

et al. 2009

J Cancer Res Clin Oncol

151

124

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“…Previous studies have shown that COX-2 overexpression has a significantly central role to in cancer development by promoting cell proliferation, decreasing apoptosis rate, and increasing invasive and metastatic potential of the primary tumor [37–39]. To clarify the mechamism of CS-6 from Chansu used as an anti-cancer agent, we investigated whether COX-2 plays an important role in CS-6 bioactive function, and found CS-6 could inhibit COX-2 expression, along with inhibiting NSCLC viability, migration and colony formation.…”

Section: Discussionmentioning

confidence: 99%

Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells

Guo

et al. 2014

Mol Cancer

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BackgroundGamabufotalin (CS-6), a major bufadienolide of Chansu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, the underlying mechanism of CS-6 involved in anti-tumor activity remains poorly understood.MethodsThe biological functions of gamabufotalin (CS-6) were investigated by migration, colony formation and apoptosis assays in NSCLC cells. The nuclear localization and interaction between transcriptional co-activator p300 and NF-κB p50/p65 and their binding to COX-2 promoter were analyzed after treatment with CS-6. Molecular docking study was used to simulate the interaction of CS-6 with IKKβ. The in vivo anti-tumor efficacy of CS-6 was also analyzed in xenografts nude mice. Western blot was used to detect the protein expression level.ResultsGamabufotalin (CS-6) strongly suppressed COX-2 expression by inhibiting the phosphorylation of IKKβ via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. In addition, CS-6 induced apoptosis by activating the cytochrome c and caspase-dependent apoptotic pathway. Moreover, CS-6 markedly down-regulated the protein levels of COX-2 and phosphorylated p65 NF-κB in tumor tissues of the xenograft mice, and inhibited tumor weight and size.ConclusionsOur study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.

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Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Cited by 34 publications

References 28 publications

Key feature of the catalytic cycle of TNF-α converting enzyme involves communication between distal protein sites and the enzyme catalytic core

Key feature of the catalytic cycle of TNF-α converting enzyme involves communication between distal protein sites and the enzyme catalytic core

Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy

Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells

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