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Mu opioid receptors may increase tumor progression

Between 1970 and 1994, well over 1 million people died as a consequence of breast cancer in the US alone. Consequently the search for new targets remains intense. New targets should be able to slow the growth and spread of tumors while at the same time being able to maintain or improve quality of life. One of the most important quality of life issues is freedom from cancer pain. Morphine is one such medication commonly used to treat pain in several medical conditions including cancer. A variety of cancer cell lines including MCF7 cancer cell lines have been shown to express mu receptors and these receptors have been persistently suggested to contribute to tumor progression and indeed antagonism of these receptors can slow the growth of tumors. Now researchers at University of Minnesota have shown that morphine, in a concentration typical of that observed in patients' blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. It does so by activating mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation via Gi/Go-coupled G protein receptors and nitric oxide in these microvascular endothelial cells. Other contributing effects of morphine include activation of the survival signal PKB/Akt, inhibition of apoptosis, and promotion of cell cycle progression by increasing cyclin D1. Consistent with these effects, morphine in clinically relevant doses promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression. These results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers. This finding is particularly interesting in the context of a DiscoveryDossier published by LeadDiscovery last year in which we suggested that kappa opioid receptor agonists may be preferable to mu agonists as treatments of breast cancer since not only are they effective analgesics in women but they also reduce neoplastic cell proliferation.

Morphine Stimulates Angiogenesis by Activating Proangiogenic and Survival-promoting Signaling and Promotes Breast Tumor Growth

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