Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.
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.
Gupta
Kalpna
K
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. gupta014@umn.edu
Kshirsagar
Smita
S
Chang
Liming
L
Schwartz
Robert
R
Law
Ping-Y
PY
Yee
Doug
D
Hebbel
Robert P
RP
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013268:Stimulation, Chemical
D000701:Analgesics, Opioid; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D009020:Morphine; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases