The NK-1 receptor antagonist L-732,138 induces apoptosis in human gastrointestinal cancer cell lines

Gastric and colon cancer cells express the neurokinin-1 receptor (NK-1R) and the peptide substance P (SP), after binding to this receptor, elicits the proliferation of gastrointestinal cancer cells and an antiapoptotic effect. In these cells, NK-1R antagonists (L-733,060: a piperidine derivative; aprepitant: a morpholine derivative) block, after binding to the NK-1R, the action of SP and exert an antiproliferative action, both antagonists promote apoptosis and the death of cancer cells. However, it is currently unknown whether tryptophan derivative NK-1R antagonists (e.g., L-732,138) exert an antiproliferative effect against gastrointestinal cancer cells. L-732,138, L-733,060 and aprepitant being structurally unrelated compounds show a high specificity for the NK-1R. To determine the number of viable cells, a Coulter counter was performed. For evaluation of tumor cell viability, an MTS colorimetric method was conducted. For apoptosis, a DAPI stain was carried out. L-732,138 blocked, in a concentration-dependent manner, the proliferation of gastrointestinal cancer cells (IC50: 75.28 and IC100: 127.4 for human SW-403 colon carcinoma cell line; IC50: 76.8 and IC100: 157.2 for 23132-87 gastric carcinoma cell line. Level of significance: p≤0.01). The antitumor effect elicited by L-732,138 was via the NK-1R and, in addition, 72.1% and 59.3% apoptotic cells (chromatin condensation and nuclear fragmentation) were respectively found in gastric and colon cancer cell lines when L-732,138 (at IC100 concentration) was administered. It seems that the NK-1R is an emerging drug target for the treatment of gastrointestinal cancer and that the tryptophan derivative NK-1R antagonist L-732,138 must be considered as an anticancer drug in gastrointestinal cancer.