Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231.
We demonstrate that neurokinin A (NKA) and substance P (SP) play a role in the proliferation of the estrogen receptor-negative (ER-) cell line MDA-MB-231, a human breast carcinoma expressing both NK-1 and NK-2 receptors. In vitro experiments showed that the specific receptor antagonists MEN 11,467 (NK-1) and nepadutant (MEN 11,420; NK-2) inhibited tumor cell proliferation, and blocked the stimulatory effect of SP and NKA. Anti-tumoral activity of NK-1 and NK-2 receptor antagonists was demonstrated in nude mice, measuring growth inhibition of MDA-MB-231 tumor cells xenografted s.c. and by using the hollow-fiber assay. In both systems a significant inhibition was found when compounds were administered at 5 mg/kg i.v. every day for 2 weeks. Results obtained from both these models suggest that the in vivo activity of NK-1 and NK-2 antagonists may be a result of a cytostatic effect rather than a cytotoxic effect. Our results suggest that the control of breast carcinoma (ER-) growth by tachykinin receptor antagonists may become a new form of targeted therapy for these human tumors.
Bigioni
Mario
M
Department of Pharmacology, Menarini Ricerche SpA, Pomezia, Italy. mbigioni@menarini-ricerche.it
Benzo
Alfredina
A
Irrissuto
Clelia
C
Maggi
Carlo Alberto
CA
Goso
Cristina
C
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003514:Cyclohexylamines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000235:genetics; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D007211:Indoles; C107754:MEN 11420; C121095:MEN 11467; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D013373:Substance P; D015288:Neurokinin A