Abstract
Matrix metalloproteinases (MMP) are ubiquitous enzymes involved in extracellular matrix remodeling, and as a consequence in a number of physiological and pathological states, including development, wound healing and cancer. A crucial feature of cancer progression and metastasis is the disruption of extracellular matrix, and spreading of proliferating cancer cells. Modulation of MMP is a main target of cancer research. Using the mouse fibrosarcoma cell line WEHI 164, producing high amounts of MMP-2, we investigated whether we could modulate its production. We report that MMP-2 is under the control of nitric oxide (NO)/nitric oxide synthase (NOS) system. In addition, we show that NOS activity is controlled by opioids in a non-opioid receptor-related manner. Finally, we provide evidence that morphine, when administrated at low, non-toxic concentrations (<10(-9) M) attenuates MMP-2 activity. We conclude that, as morphine is able to decrease metalloproteinase activity via the NO/NOS system, it may have a place in the treatment of several sarcomas including fibrosarcoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Proliferation / drug effects
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Diprenorphine / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Fibrosarcoma / metabolism
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Fibrosarcoma / pathology
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Flow Cytometry
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase Inhibitors
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Mice
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Mice, Inbred BALB C
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Morphine / pharmacology*
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NG-Nitroarginine Methyl Ester / pharmacology
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Narcotic Antagonists / pharmacology
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Opioid / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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S-Nitroso-N-Acetylpenicillamine / pharmacology
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Tumor Cells, Cultured
Substances
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Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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Narcotic Antagonists
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RNA, Messenger
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Receptors, Opioid
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Diprenorphine
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Nitric Oxide
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Morphine
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S-Nitroso-N-Acetylpenicillamine
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Nitric Oxide Synthase
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Matrix Metalloproteinase 2
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NG-Nitroarginine Methyl Ester