The NK-1 receptor is expressed in human leukemia and is involved in the antitumor action of aprepitant and other NK-1 receptor antagonists on acute lymphoblastic leukemia cell lines.
Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce cell proliferation and cell inhibition in human cancer cell lines. In acute lymphoblastic leukemia (ALL), substance P is expressed in human blast cells. However, the possible presence of NK-1 receptors in human ALL and the issue of whether the antitumor action of NK-1 receptor antagonists is exerted or not on human ALL (T-ALL BE-13 and B-ALL SD-1 cell lines) remain unknown. An immunoblot analysis was performed and an in vitro study of the cytotoxicity of three NK-1 receptor antagonists (L-733,060, L-732,138, aprepitant) was carried out on both cell lines. NK-1 receptors were found in those cell lines, and both expressed mRNA for this receptor. Using a knockdown method, we demonstrate that NK-1 receptors are involved in the viability of tumor cells. TAC1R cDNA was detected in the ALL cell lines by real-time quantitative RT-PCR. We also observed that the three NK-1 receptor antagonists elicited the inhibition of ALL cell growth; that the specific antitumor action of the NK-1 receptor antagonists occurs through the NK-1 receptor, and that ALL cell death is due to apoptosis. These findings suggest that NK-1 receptor antagonists could be considered as new antitumor drugs for the treatment of human ALL.
Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla, Spain. mmunoz@cica.es
Miguel
M
Muñoz
Ana
A
González-Ortega
Rafael
R
Coveñas
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077608:Aprepitant; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D000077608:Aprepitant; D013373:Substance P; D014364:Tryptophan