Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth

Kalpna Gupta, Smita Kshirsagar, Liming Chang, Robert Schwartz, Ping-Yee Law, Douglas Yee, Robert P Hebbel

Research output: Contribution to journalArticlepeer-review

412 Scopus citations

Abstract

Morphine is used to treat pain in several medical conditions including cancer. Here we show 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.

Original languageEnglish (US)
Pages (from-to)4491-4498
Number of pages8
JournalCancer Research
Volume62
Issue number15
StatePublished - Aug 1 2002

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