The Neurokinin-1 Receptor: A Promising Antitumor Target

Abstract

The important role played by the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer is reviewed: this includes tumor cell proliferation and migration, anti-apoptotic mechanisms, and angiogenesis. SP, through the NK-1R, behaves as a universal mitogen in cancer cells. The NK-1R is overexpressed in tumor cells and, in addition, affects the viability of cancer cells. NK-1R antagonists counteract all the previous actions mediated by SP through NK-1R. In a concentration-dependent manner, these antagonists promote tumor cell death by apoptosis. Therefore, NK-1R is a potential and promising therapeutic target for cancer treatment by using NK-1R antagonists (e.g., aprepitant) alone or in combination therapy with chemotherapy or radiotherapy.

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

“…SP is the most studied tachykinin, including its implication in cancer [ 1 , 5 ]. However, other main tachykinins are less studied; thus, the participation of both NKA and NKB in cancer is reviewed ( Table 1 ).…”

“…The involvement of peptidergic systems in cancer has attracted increasing interest in the last few years. Peptides such as substance P (a full review focused on its participation in cancer was recently published [ 5 ]), neurotensin, orexin, angiotensin II, neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, adrenomedullin, adrenomedullin 2 or intermedin, and amylin contribute to cancer development [ 1 , 2 , 6 ]. These peptides promote the mitogenesis/migration of tumor cells, exert an antiapoptotic action, and stimulate the growth of blood vessels and lymphangiogenesis.…”

“…However, some peptides such as neuropeptide Y, orexin, and vasoactive intestinal peptide also exert an anticancer effect [ 7 ]. Furthermore, tumor cells release peptides acting through autocrine, paracrine, and endocrine (tumor mass) mechanisms [ 1 , 2 , 3 , 5 , 6 , 8 , 9 , 10 , 11 ]. While some peptides (e.g., the heptapeptide angiotensin (1-7)) exert an anticancer effect, others (e.g., galanin) promote both proliferative and antiproliferative actions on tumor cells [ 3 ].…”

“…In addition, the overexpression of these receptors can be used as a prognostic biomarker [ 1 ]. The overexpression of peptidergic systems has been associated with higher tumor aggressiveness, tumor size, poor prognosis, worse sensitivity to chemotherapy agents, and increased relapse risk [ 1 , 5 ]. Peptide antagonists promote apoptosis in tumor cells, block the migration of cancer cells, and inhibit angiogenesis.…”

“…Because peptide receptors are potential new targets in cancer treatment, peptide antagonists are promising antitumor drugs. Because the involvement of substance P in cancer through the neurokinin-1 receptor is widely known [ 5 ], this review aims to update the findings regarding the involvement of the main peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide) systems in the mitogenesis, migration, and invasion of tumor cells, angiogenesis, and lymphangiogenesis; moreover, according to the data reported, this review suggests anticancer therapeutic strategies targeting tachykinin and calcitonin peptidergic systems. The signal transduction pathways, mediated by the different tachykinin/calcitonin receptors involved, are reviewed, along with the structure and dynamics of these receptors.…”