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Cancers
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Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer
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Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20743

Special Issue Editors

Prof. Dr. Rafael Coveñas Rodríguez

E-Mail Website
Guest Editor
Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neuroscience of Castilla and León (INCYL), University of Salamanca, c/Pintor Fernando Gallego 1, 37007 Salamanca, Spain
Interests: cancer and anticancer peptides; substance P/neurokinin-1 receptor system; neurokinin-1 receptor antagonists
Special Issues, Collections and Topics in MDPI journals
Dr. Miguel Muñoz Sáez

E-Mail Website
Guest Editor
Hospital Infantil Virgen del Rocío, Unidad de Cuidados Intensivos Pediátricos, Av. Manuel Siurot s/n, 41013 Sevilla, Spain
Interests: substance P; neurokinin-1 receptor; neurokinin-1 receptor antagonist; aprepitant; cancer; tumor; antitumor; apoptosis; metastasis; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, the knowledge on the involvement of peptides in cancer has attracted increasing interest. This has opened up new research lines and possibilities to improve cancer diagnosis and to explore new therapeutic strategies targeting tumor-specific molecular derangements. It is important to identify new molecular targets to block tumor development and new compounds capable of specifically destroying cancer cells must be investigated.

The undecapeptide substance P, widely distributed by the whole body, is a member of the tachykinin family of peptides. Substance P binds preferentially to the neurokinin-1 receptor and the undecapeptide has been involved in many biological functions, including cancer. Substance P, via the neurokinin-1 receptor, promotes the mitogenesis and migration of tumor cells, exerts an antiapoptotic action and stimulates the growth of blood vessels by promoting the mitogenesis of endothelial cells. Tumor cells express substance P and overexpress the neurokinin-1 receptor which is involved in the viability of tumor cells. In this sense, the absence of the stimulus mediated by substance P using neurokinin-1 receptor inhibitors (genetic or pharmacological treatment) promoted the death of cancer cells by apoptosis. Substance P mediates a common mechanism for the proliferation of tumor cells and the overexpression of the neurokinin-1 receptor in cancer cells opens up the possibility for a specific therapeutic treatment against these cells.

Neurokinin-1 receptor antagonists show an antitumor activity, inducing apoptosis in tumor cells, inhibiting angiogenesis and blocking the migration of cancer cells. These antagonists act as broad-spectrum antineoplastic drugs and exert a universal action, apoptosis, in tumor cells. In combination therapy (chemotherapy), neurokinin-1 receptor antagonists exert a synergic effect and decrease the side-effects promoted by cytostatics.

The neurokinin-1 receptor is a new promising target in cancer treatment and neurokinin-1 receptor antagonists are a promising generation of antitumor drugs. To increase the current knowledge on the role played by the substance P/neurokinin-1 receptor system in cancer, this Special Issue will highlight basic, pre-clinical and clinical aspects on the involvement of the substance P/neurokinin-1 receptor system in cancer development and it will be also focused on the promising use of neurokinin-1 receptor antagonists as a new antitumor strategy.

Prof. Dr. Rafael Coveñas Rodríguez
Dr. Miguel Muñoz Sáez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • substance P
  • neurokinin-1 receptor
  • neurokinin-1 receptor antagonist
  • cancer
  • tumor development
  • antitumor
  • apoptosis
  • metastasis
  • angiogenesis

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Published Papers (7 papers)

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Editorial

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5 pages, 216 KiB  
Editorial
Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer
by Rafael Coveñas and Miguel Muñoz
Cancers 2022, 14(14), 3539; https://doi.org/10.3390/cancers14143539 - 21 Jul 2022
Cited by 15 | Viewed by 1916
Abstract
New, promising molecular targets to block tumor development and new compounds capable of specifically destroying cancer cells must be urgently investigated [...] Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)

Research

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15 pages, 2737 KiB  
Article
Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis
by Emma Rodriguez, Guangsheng Pei, Zhongming Zhao, Sang T. Kim, Alexis German and Prema Robinson
Cancers 2021, 13(15), 3871; https://doi.org/10.3390/cancers13153871 - 31 Jul 2021
Cited by 13 | Viewed by 2947
Abstract
Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in [...] Read more.
Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
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19 pages, 10532 KiB  
Article
Identification of the Neurokinin-1 Receptor as Targetable Stratification Factor for Drug Repurposing in Pancreatic Cancer
by Iris Beirith, Bernhard W. Renz, Shristee Mudusetti, Natalja Sergejewna Ring, Julian Kolorz, Dominik Koch, Alexandr V. Bazhin, Michael Berger, Jing Wang, Martin K. Angele, Jan G. D’Haese, Markus O. Guba, Hanno Niess, Joachim Andrassy, Jens Werner and Matthias Ilmer
Cancers 2021, 13(11), 2703; https://doi.org/10.3390/cancers13112703 - 30 May 2021
Cited by 12 | Viewed by 4311
Abstract
The SP/NK1R-complex plays an important role in tumor proliferation. Targeting of the neurokinin-1 receptor in previous studies with its antagonist aprepitant (AP) resulted in anti-tumoral effects in colorectal cancer and hepatoblastoma. However, there is still a lack of knowledge regarding its effects on [...] Read more.
The SP/NK1R-complex plays an important role in tumor proliferation. Targeting of the neurokinin-1 receptor in previous studies with its antagonist aprepitant (AP) resulted in anti-tumoral effects in colorectal cancer and hepatoblastoma. However, there is still a lack of knowledge regarding its effects on pancreatic cancer. Therefore, we treated human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, DanG, HuP-T3, Panc-1, and MIA PaCa-2) and their cancer stem cell-like cells (CSCs) with AP and analyzed functional effects by MTT-, colony, and sphere formation assays, respectively; moreover, we monitored downstream mechanisms by flow cytometry. NK1R inhibition resulted in dose-dependent growth reduction in both CSCs and non-CSCs without induction of apoptosis in most PDAC cell lines. More importantly, we identified striking AP dependent cell cycle arrest in all parental cells. Furthermore, gene expression and the importance of key genes in PDAC tumorigenesis were analyzed combining RT-qPCR in eight PDAC cell lines with publicly available datasets (TCGA, GEO, CCLE). Surprisingly, we found a better overall survival in patients with high NK1R levels, while at the same time, NK1R was significantly decreased in PDAC tissue compared to normal tissue. Interestingly, there is currently no differentiation between the isoforms of NK1R (truncated and full; NK1R-tr and -fl) in any of the indicated public transcriptomic records, although many publications already emphasize on important regulatory differences between the two isoforms of NK1R in many cancer entities. In conclusion, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies. Furthermore, we presume PDAC patients with high expressions of NK1R-tr might benefit from treatment with AP to improve chemoresistance. Therefore, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies. Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
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12 pages, 1929 KiB  
Article
Substance P Antagonism Prevents Chemotherapy-Induced Cardiotoxicity
by Ashiq Legi, Emma Rodriguez, Thomas K. Eckols, Cyrus Mistry and Prema Robinson
Cancers 2021, 13(7), 1732; https://doi.org/10.3390/cancers13071732 - 6 Apr 2021
Cited by 15 | Viewed by 2978
Abstract
Background: Doxorubicin (DOX), used in chemotherapeutic regimens in many cancers, has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. We determined the role of Substance P (SP), a neuropeptide and its high affinity receptor, [...] Read more.
Background: Doxorubicin (DOX), used in chemotherapeutic regimens in many cancers, has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. We determined the role of Substance P (SP), a neuropeptide and its high affinity receptor, NK-1R in chemotherapy associated cardiotoxicity in mice. We determined if NK-1R antagonism will prevent DOX-induced cardiotoxicity in vivo. Methods: C57BL/6 mice (6- week old male) were injected intraperitoneally with DOX (5 mg per kilogram of body weight once a week for 5 weeks) with or without treatment with aprepitant (a NK-1R antagonist, Emend, Merck & Co., Kenilworth, NJ, USA). Five different dosages of aprepitant were administered in the drinking water five days before the first injection of DOX and then continued until the end of the experiment. Each of these 5 doses are as follows; Dose 1 = 0.9 µg/mL, Dose 2 = 1.8 µg/mL, Dose 3 = 3.6 µg/mL, Dose 4 = 7.2 µg/mL, Dose 5 = 14.4 µg/mL. Controls consisted of mice injected with PBS (instead of DOX) with or without aprepitant treatment. The experiment was terminated 5 weeks post-DOX administration and various cardiac functional parameters were determined. Following euthanization, we measured heart weight to body weight ratios and the following in the hearts, of mice treated with and without DOX and aprepitant; (a) levels of SP and NK1R, (b) cardiomyocyte diameter (to determine evidence of cardiomyocyte hypertrophy), (c) Annexin V levels (to determine evidence of cardiac apoptosis), and (d) ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) (to determine evidence of oxidative stress). Results: We demonstrated that the levels of SP and NK1R were significantly increased respectively by 2.07 fold and 1.86 fold in the hearts of mice treated with versus without DOX. We determined that DOX-induced cardiac dysfunction was significantly attenuated by treatment with aprepitant. Cardiac functional parameters such as fractional shortening (FS), ejection fraction (EF) and stroke volume (SV) were respectively decreased by 27.6%, 21.02% and 21.20% compared to the vehicle treated group (All, p < 0.05, ANOVA). Importantly, compared to treatment with DOX alone, treatment with lower doses of aprepitant in DOX treated mice significantly reduced the effects of DOX on FS, EF and SV to values not significantly different from sham (vehicle treated) mice (All, p < 0.05, ANOVA). The levels of, apoptosis marker (Annexin V), oxidative stress (ratio of GSH with GSSG) and cardiomyocyte hypertrophy were respectively increased by 47.61%, 91.43% and 47.54% in the hearts of mice treated with versus without DOX. Compared to the DOX alone group, treatment with DOX and Dose 1, 2 and 3 of aprepitant significantly decreased the levels of each of these parameters (All p < 0.05, ANOVA). Conclusions: Our studies indicate that the SP/NK1-R system is a key mediator that induces, DOX-induced, cardiac dysfunction, cardiac apoptosis, cardiac oxidative stress and cardiomyocyte hypertrophy. These studies implicate that NK-1R antagonists may serve as a novel therapeutic tool for prevention of chemotherapy induced cardiotoxicity in cancer. Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
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Review

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17 pages, 1264 KiB  
Review
Neurokinin-1 Receptor (NK-1R) Antagonists as a New Strategy to Overcome Cancer Resistance
by Marilina García-Aranda, Teresa Téllez, Lauraine McKenna and Maximino Redondo
Cancers 2022, 14(9), 2255; https://doi.org/10.3390/cancers14092255 - 30 Apr 2022
Cited by 18 | Viewed by 3669
Abstract
Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within [...] Read more.
Nowadays, the identification of new therapeutic targets that allow for the development of treatments, which as monotherapy, or in combination with other existing treatments can contribute to improve response rates, prognosis and survival of oncologic patients, is a priority to optimize healthcare within sustainable health systems. Recent studies have demonstrated the role of Substance P (SP) and its preferred receptor, Neurokinin 1 Receptor (NK-1R), in human cancer and the potential antitumor activity of NK-1R antagonists as an anticancer treatment. In this review, we outline the relevant studies published to date regarding the SP/NK-1R complex as a key player in human cancer and also evaluate if the repurposing of already marketed NK-1R antagonists may be useful in the development of new treatment strategies to overcome cancer resistance. Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
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Other

1 pages, 159 KiB  
Erratum
Erratum: Rodriguez et al. Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis. Cancers 2021, 13, 3871
by Emma Rodriguez, Guangsheng Pei, Zhongming Zhao, Sang T. Kim, Alexis German and Prema Robinson
Cancers 2021, 13(20), 5178; https://doi.org/10.3390/cancers13205178 - 15 Oct 2021
Cited by 2 | Viewed by 1186
Abstract
One contributor’s name was missing in the original version of the authorship of the paper [...] Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
16 pages, 1723 KiB  
Systematic Review
Significance of the Overexpression of Substance P and Its Receptor NK-1R in Head and Neck Carcinogenesis: A Systematic Review and Meta-Analysis
by Miguel Ángel González-Moles, Pablo Ramos-García and Francisco Esteban
Cancers 2021, 13(6), 1349; https://doi.org/10.3390/cancers13061349 - 17 Mar 2021
Cited by 13 | Viewed by 2334
Abstract
The objective of our study has been, through a systematic review and meta-analysis, to increase the scientific evidence on the implications of SP and its receptor NK-1R in head and neck carcinogenesis. We searched studies published before May-2020 without date and publication language [...] Read more.
The objective of our study has been, through a systematic review and meta-analysis, to increase the scientific evidence on the implications of SP and its receptor NK-1R in head and neck carcinogenesis. We searched studies published before May-2020 without date and publication language restrictions (PubMed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (QUIPS tool). We performed heterogeneity, sensitivity, small-study effects, and subgroup analyses. A total 16 studies and 1308 cases met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same scientific rigor, finding the greatest risk of bias in the study confounding and prognostic factors measurement domains. Quantitative evaluation showed a greater SP/NK-1R overexpression in malignant head and neck lesions compared to benign lesions (p = 0.02), and that expression was observed in malignant salivary gland pathology. Likewise, we found a higher overexpression of NK-1R compared to SP (p = 0.02). In conclusion, the results of this systematic review and meta-analysis show evidence that the upregulation of SP and NK-1R are oncogenic events involved in head and neck carcinogenesis, probably acting in the early stages of malignization. In addition, there is evidence of a greater relevance of the upregulation of the NK-1R receptor compared to SP, which highlights the interest in deepening the development of targeted therapies on the receptor. Future studies assessing the relationships between SP/NK-1R among subjects with head and neck tumors could consider the recommendations given in this systematic review and meta-analysis to improve and standardize future research. Full article
(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)
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