The discovery of anthranilic acid-Based MMP inhibitors. Part 2: SAR of the 5-position and P11 groups

Levin, Jeremy I.; Chen, J.; Du, Mila T.; Hogan, Michael E.; Kincaid, Scott L.; Nelson, Frances C.; Venkatesan, Aranapakam M.; Wehr, Timothy; Zask, Arie; DiJoseph, John F.; Killar, Loran M.; Skala, Stacey; Sung, Amy; Sharr, Michele A.; Roth, Catherine; Jin, Guixian; Cowling, Rebecca; Mohler, Kendall M.; Black, Roy A.; March, Carl J.; Skotnicki, J.S.

doi:10.1016/s0960-894x(01)00419-x

Cited by 77 publications

(42 citation statements)

References 16 publications

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“…Treatments of specific pharmacological inhibitors to these MMP proteins suppressed cancer cell migration and invasion (32)(33)(34), which additionally indicates that ICAM-3 is an upstream effector to MMP proteins. Second, our results also have showed that enhancement of cell migration/invasion which was induced by ICAM-3 was composed of various components of intracellular signaling pathway.…”

Section: Discussionmentioning

confidence: 92%

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

Park

et al. 2009

Int J Oncol

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Abstract.We have previously reported that intercellular adhesion molecule-3 (ICAM-3) is associated with an increase of cellular radio-resistance and cancer cell proliferation. In this study, we hypothesized that ICAM-3 has an additional effect on cancer cell migration and invasion because molecules induced by ICAM-3 are known as regulators of cell migration and invasion. To examine this hypothesis, we used NCI-H1299 non-small cell lung cancer (NSCLC) cell line (p53 and PTEN null cell) and constructed an ICAM-3-over-expressing stable transfectant, which exhibited increased cell migration and invasion. The increased migration and invasion resulted from up-regulation of expression and activities of MMP-2 and MMP-9. ICAM-3 also increased Akt phosphorylation, which caused an increase in cellular migration/invasion and MMP activities. Activity of several transcriptional factors located downstream in the Akt pathway was also tested, and constitutive activation of adenosine 3', 5'-monophosphate response element-binding protein (CREB) by ICAM-3 was detected. Blockage of the Akt pathway attenuated CREB activation, and a decrease in CREB expression reduced cellular migration/invasion and activity of MMPs. This result indicates that CREB functions in the signaling pathway between Akt and MMP. We also showed ICAM-3-induced cell migration and invasion in NCI-H460 NSCLC cells (wild-type p53 and PTEN cell) through the same signaling pathway. Taken together, our findings suggest that ICAM-3 stimulates cancer cell migration/ invasion via ICAM-3/Akt/CREB/MMP pathway regardless of p53 and PTEN status, and this reflects the possibility that ICAM-3 could be considered as a candidate for anti-cancer drug development and as a cancer diagnostic marker.

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Section: Discussionmentioning

confidence: 92%

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

Park

et al. 2009

Int J Oncol

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“…*P < 0.05 and **P < 0.01, by 2-tailed Student's t test. To assess the impact of MMP-9 inhibition on retinal permeability in diabetic mice, we used an anthranilic acid-based inhibitor of MMP-9 (Type I MMP-9 inhibitor; Calbiochem) (41). Intravitreal injections of the inhibitor at 6 and 7 weeks of diabetes (final vitreous concentration of 5 nmol/l) led to a significant reduction of diabetes-induced permeability by approximately 39% (MMP-9 inhibitor 39.11%; 1.000 ± 0.1050 [STZ], 0.6089 ± 0.1002 [treated STZ], P < 0.05, n = 12 mice) ( Figure 7G).…”

Section: Resultsmentioning

confidence: 99%

Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy

Miloudi¹,

Binet²,

Wilson³

et al. 2016

Journal of Clinical Investigation

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“…It inhibits MMP-1 at IC50 = 1.05 µM. This inhibitor complexes with the zinc cofactor that is required to keep MMP-9 in an active state (Levin et al 2001). The MMP-9 inhibitor was added to the Epidermalization III medium (beginning at day 11) in increasing doses from 0.5 nM to 500 nM.…”

Section: Pharmacological Mmp-9 and Akt Inhibitionmentioning

confidence: 99%

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

Okawa¹,

Michaylira²,

Kalabis³

et al. 2007

Genes Dev.

158

161

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Esophageal cancer is a prototypic squamous cell cancer that carries a poor prognosis, primarily due to presentation at advanced stages. We used human esophageal epithelial cells as a platform to recapitulate esophageal squamous cell cancer, thereby providing insights into the molecular pathogenesis of squamous cell cancers in general. This was achieved through the retroviral-mediated transduction into normal, primary human esophageal epithelial cells of epidermal growth factor receptor (EGFR), the catalytic subunit of human telomerase (hTERT), and p53 R175H, genes that are frequently altered in human esophageal squamous cell cancer. These cells demonstrated increased migration and invasion when compared with control cells. When these genetically altered cells were placed within the in vivo-like context of an organotypic three-dimensional (3D) culture system, the cells formed a high-grade dysplastic epithelium with malignant cells invading into the stromal extracellular matrix (ECM). The invasive phenotype was in part modulated by the activation of matrix metalloproteinase-9 (MMP-9). Using pharmacological and genetic approaches to decrease MMP-9, invasion into the underlying ECM could be suppressed partially. In addition, tumor differentiation was influenced by the type of fibroblasts within the stromal ECM. To that end, fetal esophageal fibroblasts fostered a microenvironment conducive to poorly differentiated invading tumor cells, whereas fetal skin fibroblasts supported a well-differentiated tumor as illustrated by keratin "pearl" formation, a hallmark feature of well-differentiated squamous cell cancers. When inducible AKT was introduced into fetal skin esophageal fibroblasts, a more invasive, less-differentiated esophageal cancer phenotype was achieved. Invasion into the stromal ECM was attenuated by genetic knockdown of AKT1 as well as AKT2. Taken together, alterations in key oncogenes and tumor suppressor genes in esophageal epithelial cells, the composition and activation of fibroblasts, and the components of the ECM conspire to regulate the physical and biological properties of the stroma.[Keywords: Cell migration and invasion; tumor microenvironment; EGFR; p53; MMP-9; AKT] Supplemental material is available at http://www.genesdev.org. Received February 22, 2007; revised version accepted September 5, 2007. 8 These authors contributed equally to this work. 9Corresponding author. E-MAIL anil2@mail.med.upenn.edu; FAX (215) 573-5412. Article is online at http://www.genesdev.org/cgi

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The discovery of anthranilic acid-Based MMP inhibitors. Part 2: SAR of the 5-position and P11 groups

Cited by 77 publications

References 16 publications

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy

The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation

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