Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231

Anticancer Drugs. 2005 Nov;16(10):1083-9. doi: 10.1097/00001813-200511000-00007.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Carcinoma / drug therapy*
  • Carcinoma / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclohexylamines / chemistry
  • Cyclohexylamines / pharmacology
  • Cyclohexylamines / therapeutic use*
  • Female
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neurokinin A / antagonists & inhibitors
  • Neurokinin A / pharmacology
  • Neurokinin-1 Receptor Antagonists*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, Neurokinin-1 / agonists
  • Receptors, Neurokinin-1 / genetics
  • Receptors, Neurokinin-2 / agonists
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Receptors, Neurokinin-2 / genetics
  • Substance P / antagonists & inhibitors
  • Substance P / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cyclohexylamines
  • Indoles
  • MEN 11420
  • MEN 11467
  • Neurokinin-1 Receptor Antagonists
  • Peptides, Cyclic
  • RNA, Messenger
  • Receptors, Neurokinin-1
  • Receptors, Neurokinin-2
  • Substance P
  • Neurokinin A