Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor.
OBJECTIVE
Vapreotide, a synthetic analog of somatostatin, has analgesic activity most likely mediated through the blockade of neurokinin-1 receptor (NK1R), the substance P (SP)-preferring receptor. The ability of vapreotide to interfere with other biological effects of SP has yet to be investigated.


METHODS
We studied the ability of vapreotide to antagonize NK1R in three different cell types: immortalized U373MG human astrocytoma cells, human monocyte-derived macrophages (MDM) and a human embryonic kidney cell line, HEK293. Both U373MG and MDM express endogenous NK1R while HEK293 cells, which normally do not express NK1R, are stably transformed to express human NK1R (HEK293-NK1R).


RESULTS
Vapreotide attenuates SP-triggered intracellular calcium increases and nuclear factor-κB activation in a dose-dependent manner. Vapreotide also inhibits SP-induced interleukin-8 and monocyte chemotactic protein-1 production in HEK293-NK1R and U373MG cell lines. Vapreotide inhibits HIV-1 infection of human MDM in vitro, an effect that is reversible by SP pretreatment.


CONCLUSIONS
Our findings indicate that vapreotide has NK1R antagonist activity and may have a potential application as a therapeutic intervention in HIV-1 infection.
Division of Allergy and Immunology, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
Sergei
S
Spitsin
Florin
F
Tuluc
John
J
Meshki
Jian
J
Ping Lai
Richard
R
Tustin Iii
Steven D
SD
Douglas
D000700:Analgesics / Q000494:pharmacology*; D000077608:Aprepitant; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014162:Transfection; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D000700:Analgesics; D018932:Chemokine CCL2; D016207:Cytokines; D009025:Morpholines; D016328:NF-kappa B; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D017481:Receptors, Somatostatin; D054301:gag Gene Products, Human Immunodeficiency Virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D000077608:Aprepitant; C051458:vapreotide; D013373:Substance P; D013004:Somatostatin; C093733:somatostatin receptor 2; D002118:Calcium