The substance P/neurokinin-1 receptor system in lung cancer: Focus on the antitumor action of neurokinin-1 receptor antagonists
Highlights
► SP/NK-1R antagonists respectively induces/inhibit proliferation in lung cancer cells. ► NK-1 receptor antagonists induce apoptosis in human lung cancer cells. ► Human lung cancer cells overexpress the tachykinin 1 gene. ► The NK-1 receptor is involved in the viability of human lung cancer cells. ► Substance P and NK-1 receptors are expressed in human lung cancer samples.
Introduction
Lung cancer is the first cause of cancer-related death in western world. Despite multiple trials with cytotoxic chemotherapeutic agents, anti-growth factor-signaling agents and/or radiotherapy, the last two decades have seen no significant progress in extending the survival of patients suffering the disease [10]. Cytostatic drugs show a low safety profile and severe side effects, since they are not specific to tumor cells. Research should focus on drugs with the same or greater anti-tumor action but with fewer side effects. This can only be achieved if the drug is specific against tumor cells and researchers are therefore seeking to identify novel molecular targets for blocking tumor growth.
The expression and secretion of peptides by tumors has attracted increasing interest, and there are data suggesting that the substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in cancer development [19], [20], [24]: the number of NK-1Rs expressed in normal human cells is lower than that expressed in human tumoral cells; the expression of NK-1Rs is correlated with the degree of malignancy; the activation of NK-1Rs by SP induces mitogenesis in human tumor cell lines; the migration of tumor cells, a crucial requirement for invasion and metastasis, is regulated by SP signals, and NK-1R antagonists exert an antitumoral action against human cancer cell lines. Moreover, NK-1R antagonists do not usually have serious side effects. One such antagonist, the drug aprepitant, is used in clinical practice as antiemetic [2]. Thus, there are sufficient data suggesting that the NK-1R could be a new promising target in human cancer treatment and that NK-1R antagonists should be designed as novel therapeutic agents.
Currently, a few studies implicating the SP/NK-1R system in lung cancer have been reported: synthetic analogs of SP (identified as antagonists of SP-mediated cellular effects) induce cell death by apoptosis in both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cells [12], [26], [28], [32]. To our knowledge, there are many unknown issues regarding the involvement of the SP/NK-1R system in SCLC and NSCLC. Thus, the aims of this study are to demonstrate: (1) in vitro the presence of NK-1Rs and their isoforms in the H-69 SCLC and COR-L23 NSCLC cell lines; (2) that both cell lines express mRNA for the NK-1R and overexpress the tachykinin 1 gene; (3) that the NK-1R is involved in their viability; (4) that SP induces their proliferation; (5) that NK-1R antagonists, other than synthetic analogs of SP, such as L-733,060, L-732,138 and the drug aprepitant, inhibit the growth of both cell lines; (6) that the specific antitumor action of such antagonists occurs through the NK-1R and produces apoptosis in both cancer cell lines; and (7) the presence of NK-1Rs and SP in human SCLC and NSCLC samples. The data suggest that the NK-1R is a promising new target in the treatment of lung cancer.
Section snippets
Cell cultures and drug treatments
We used H-69 SCLC and COR-L23 NSCLC lung cancer cell lines (European Collection of Cell Cultures). These cells were maintained as previously reported [23].
Three NK-1R antagonists were used: L-733,060, L-732,138 and aprepitant. In order to determine the IC50, different concentrations (5–40 μM) of L-733,060; (10–100 μM) of L-732,138; (5–50 μM) of aprepitant were evaluated. Different concentrations of SP (1, 5, 10, 100 and 500 nM) were used. The most mitogenic nanomolar SP concentration for each cell
NK-1 receptors
Three similar bands (isoforms of the NK-1R of about 34, 58 and 75 kDa) were observed in the H-69 SCLC and COR-L23 NSCLC cell lines and an additional 46-kDa band was also observed in the former cell line (Fig. 1A).
With PCR analyses we observed that the H-69 SCLC and COR-L23 NSCLC tumor cell lines expressed mRNA for the tachykinin NK-1R (Fig. 1B). Real-time quantitative RT-PCR was performed to analyze NK-1R expression using beta-actin as an internal control. The mean NK-1R/beta-actin ratio was 0.6 ±
Discussion
The data described here are in agreement with those of previous studies, in which the presence of isoforms and the overexpression of the NK-1R have been reported in several human cancer cell lines other than SCLC/NSCLC [16], [21], [22], [23]. NK-1R expression is known to be increased 25–36-fold in human pancreatic cancer cell lines in comparison with normal controls; in glioma, NK-1Rs are overexpressed in comparison with normal cells, and tumors samples from patients with advanced tumor stages
Conclusions
In sum, we have performed an in-depth study of the involvement of the SP/NK-1R system in lung cancer. Our findings suggest that the NK-1R could be a new candidate target in the treatment of SCLC and NSCLC and that NK-1R antagonists (e.g., the drug aprepitant (Emend)) could be a novel, promising antitumor drug in lung cancer therapy, since they could exert an antitumoral action through three mechanisms: (1) an antiproliferative effect, due to the inhibition of tumor cell growth, inducing cell
Conflicts of interest
USPTO Application no. 20090012086 “Use of non-peptidic NK-1 receptor antagonists for the production of apoptosis in tumor cells” (Miguel Muñoz).
Acknowledgements
This work was supported by the Consejería de Innovacion, Ciencia y Empresa of the Regional Government of Andalucía (CTS-2247, Spain). The authors wish to thank Dr. José Palacios for providing lung cancer samples, and Mr. Manuel Sánchez and Mr. Francisco Jesus Fuentes for technical assistance and Mr. Nicholas Skinner for supervising the English text.
References (33)
- et al.
Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer
Lab Invest
(2003) - et al.
Cell proliferation associated with actions of the substance P/NK1 receptor complex in keratocystic odontogenic tumours
Oral Oncol
(2008) - et al.
Targeting growth factors in lung cancer
Chest
(2008) - et al.
Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism
J Biol Chem
(2009) - et al.
The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines
Neuropeptides
(2005) - et al.
The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines
Lab Invest
(2010) - et al.
[d-Arg1-d-Phe5, d-Trp7,9, Leu11] Substance P induces apoptosis in lung cancer cell lines in vitro
Biochem Biophys Res Commun
(1994) - et al.
NK-1 receptor gene expression is related to pain in chronic pancreatitis
Pain
(2001) - et al.
P stimulates neovascularization in vivo and proliferation of cultured endothelial cells
Microvasc Res
(1990) - et al.
A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas
J Neurochem
(2009)
Aprepitant use in children, adolescents, and young adults for the control of chemotherapy-induced nausea and vomiting (CINV)
J Pediatr Hematol Oncol
Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers
Int J Cancer
The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta-arrestin-dependent scaffolding complex
Proc Natl Acad Sci USA
A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage
Cancer Metast Rev
Stimulation of angiogenesis by substance P an interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists
Br J Pharmacol
Substance-P receptors in human primary neoplasms: tumoral and vascular localization
Int J Cancer
Cited by (66)
Why Use Aprepitant Only as a Cough Suppressant in Lung Cancer When at Higher Doses it Could Also Exert an Antitumor Action?
2022, Archivos de BronconeumologiaNew repurposed rolapitant in nanovesicular systems for lung cancer treatment: Development, in-vitro assessment and in-vivo biodistribution study
2022, European Journal of Pharmaceutical SciencesAdvances in the research and application of neurokinin-1 receptor antagonists
2024, Journal of Zhejiang University: Science BSubstance P and Neurokinin-1 Receptor System in Thyroid Cancer: Potential Targets for New Molecular Therapies
2023, Journal of Clinical Medicine