Down-regulation of trypsinogen-2 expression by chemically modified tetracyclines: Association with reduced cancer cell migration

Lukkonen, Annukka; Sorsa, Timo; Salo, Tuula; Tervahartiala, Taina; Koivunen, Erkki; Golub, Lorne M.; Simon, Sanford R.; Stenman, Ulf‐Hǎkan

doi:10.1002/(sici)1097-0215(20000515)86:4<577::aid-ijc21>3.0.co;2-j

Cited by 46 publications

(9 citation statements)

References 21 publications

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“…Doxycycline is the most potent MMP inhibitor of the approved tetracyclines [44]. In vitro studies have demonstrated effects including inhibition of transcription or activity of MMP1, MMP2 (at least in part via action on MT1-MMP), MMP8, MMP9, and MMP13 [40,[45][46][47][48][49]. Tetracyclines also have effects on the interleukin-1 system, [45,46], actions that would indirectly lead to a reduction in MMP action.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases in Endometrial Breakdown and Repair: Functional Significance in a Mouse Model1

Kaitu'u

Shen²,

Zhang³

et al. 2005

Biology of Reproduction

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Considerable correlative evidence suggests an important role for matrix metalloproteinases (MMPs) in menstruation, a process which occurs naturally in very few species. In this study, MMP expression was examined in a mouse model of endometrial breakdown and repair and the functional importance of MMPs determined. In the model, progesterone support was withdrawn from mice in which endometrial decidualization had been induced; 24 h later, endometrial breakdown was complete, and the entire decidual zone had been shed. Re-epithelialization had occurred by 36 h, and the endometrium had undergone extensive restoration toward a predecidualized state by 48 h. Immunoreactive MMP9 and MMP7 colocalized with leukocyte subsets, particularly neutrophils, whereas MMP13 staining was always extracellular. MMP3 and MMP7 were abundant during re-epithelialization in close proximity to newly reforming epithelium. The functional importance of MMPs in these processes was examined using two MMP inhibitors, doxycycline and batimistat. Both inhibitors effectively reduced MMP activity, as assessed by in situ zymography, but did not have significant effects on endometrial breakdown or repair. This study demonstrates that although MMPs are present in abundance during endometrial breakdown and repair in this mouse model, they are not the key mediators of these processes.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases in Endometrial Breakdown and Repair: Functional Significance in a Mouse Model1

Kaitu'u

Shen²,

Zhang³

et al. 2005

Biology of Reproduction

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“…Chemically modified tetracyclines (CMTs) without antibiotic activities can bind metal ions such as calcium and zinc, and to affect MMP gene transcription [157]. A high-throughput screening system identifies a small molecule 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) that can repress MMP-9 expression by antagonizing AP-1 transactivation activity [158].…”

Section: Inhibitors Of Mmps Transcriptionmentioning

confidence: 99%

Matrix metalloproteinases in tumorigenesis: an evolving paradigm

Hua

Luo

et al. 2011

Cell. Mol. Life Sci.

244

181

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Proteases are crucial for development, tissue remodeling, and tumorigenesis. Matrix metalloproteinases (MMPs) family, in particular, consists of more than 20 members with unique substrates and diverse function. The expression and activity of MMPs in a variety of human cancers have been intensively studied. MMPs have well-recognized roles in the late stage of tumor progression, invasion, and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis, e.g., in malignant transformation, angiogenesis, and tumor growth both at the primary and metastatic sites. Recent studies also suggest that MMPs play complex roles in tumor progression. While most MMPs promote tumor progression, some of them may protect the host against tumorigenesis in a context-dependent manner. MMPs have been chosen as promising targets for cancer therapy on the basis of their aberrant up-regulation in malignant tumors and their ability to promote cancer metastasis. Although preclinical studies testing the efficacy of MMP suppression in tumor models were so encouraging, the results of clinical trials in cancer patients have been rather disappointing. Here, we review the complex roles of MMPs and their endogenous inhibitors such as tissue inhibitors of metalloproteinase in tumorigenesis and strategies in suppressing MMPs.

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“…Doxycycline along with other chemically modified tetracyclines has been shown to inhibit components of the matrix metalloproteinase cascade in cancer cell lines [9]. Doxycycline has also been identified as an inhibitor of trypsinogen-2, which has been shown to be expressed in many types of human tumor cells [11]. Trypsinogen-2 is thought to play a role in cancer cell migration and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Phase II study of interferon-alpha and doxycycline for advanced renal cell carcinoma

Huie¹,

Oettel²,

Ummersen³

et al. 2005

Invest New Drugs

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Down-regulation of trypsinogen-2 expression by chemically modified tetracyclines: Association with reduced cancer cell migration

Cited by 46 publications

References 21 publications

Matrix Metalloproteinases in Endometrial Breakdown and Repair: Functional Significance in a Mouse Model1

Matrix Metalloproteinases in Endometrial Breakdown and Repair: Functional Significance in a Mouse Model1

Matrix metalloproteinases in tumorigenesis: an evolving paradigm

Phase II study of interferon-alpha and doxycycline for advanced renal cell carcinoma

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