The substance P/neurokinin-1 receptor system in lung cancer: Focus on the antitumor action of neurokinin-1 receptor antagonists

Muñoz, Miguel; González-Ortega, Ana; Rosso, Marisa; Robles‐Frías, María José; Carranza, Andrés Carranza; Salinas-Martín, Manuel Vicente; Coveñas, Rafael

doi:10.1016/j.peptides.2012.09.024

Cited by 67 publications

(54 citation statements)

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“…SP has been located in the cytoplasm and in the nucleus of tumor cells (González-Moles et al 2008;Brener et al 2009;Esteban et al 2009;Muñoz et al 2012). Moreover, the PPT1 gene is expressed more in breast cancer than in epithelial breast cells (Singh et al 2000).…”

Section: Cancermentioning

confidence: 99%

“…NK-1 receptors have also been demonstrated in human cancer cell lines and/or in primary tumors [e.g., glioma, astrocytoma, retinoblastoma, ganglioneuroblastoma, leukemia, neuroblastoma, carcinomas (pancreatic, larynx, gastric, colon, medullary thyroid, breast, oral)] (Friess et al 2003;González-Moles et al 2008;Brener et al 2009;Esteban et al 2009;Muñoz et al 2007;. It is also known that tumor cells overexpress NK-1 receptors, in comparison with non-tumor cells (Singh et al 2000;Friess et al 2003;Muñoz et al 2012) (Fig. 1) and that SP, in a concentration-dependent manner, induces tumor cell proliferation in many different human tumor cell lines (for a review, see .…”

Section: Cancermentioning

confidence: 99%

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Involvement of substance P and the NK-1 receptor in human pathology

2014

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The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also present in cells not belonging to the nervous system (immune cells, liver, lung, placenta, etc.). SP is located in all body fluids, such as blood, cerebrospinal fluid, breast milk, etc. i.e. it is ubiquitous in human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates many pathophysiological functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, vomiting, migraine, alcohol addiction, seizures and neurodegeneration. SP has been also implicated in pain, inflammation, hepatitis, hepatotoxicity, cholestasis, pruritus, myocarditis, bronchiolitis, abortus, bacteria and viral infection (e.g., HIV infection) and it plays an important role in cancer (e.g., tumor cell proliferation, antiapoptotic effects in tumor cells, angiogenesis, migration of tumor cells for invasion, infiltration and metastasis). This means that the SP/NK-1 receptor system is involved in the molecular bases of many human pathologies. Thus, knowledge of this system is the key for a better understanding and hence a better management of many human diseases. In this review, we update the involvement of the SP/NK-1 receptor system in the physiopathology of the above-mentioned pathologies and we suggest valuable future therapeutic interventions involving the use of NK-1 receptor antagonists, particularly in the treatment of emesis, depression, cancer, neural degeneration, inflammatory bowel disease, viral infection and pruritus, in which that system is upregulated.

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Section: Cancermentioning

confidence: 99%

Section: Cancermentioning

confidence: 99%

Involvement of substance P and the NK-1 receptor in human pathology

2014

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“…It has previously been reported that NK-1 receptor blockers could inhibit the growth of cancer cells, such as human epidermoid cancer cells, pancreatic cancer cells, gastrointestinal cancer cells, and lung cancer cells. [9][10][11][12] In the present study, the LSWS suppressed the growth of HepG2 cells, and down-regulated the expression of the NK-1 receptor, which indicated that an NK-1 receptordependent pathway might be involved in the LSWS-induced cancer cell growth inhibition. These findings described here for the first time the antitumor action of LSWS could be due to NK-1 receptor antagonist pharmacological profile.…”

Section: Discussionmentioning

confidence: 72%

“…Moreover, these findings are in agreement with previously described in other different carcinoma cell lines. [9][10][11][12] Apart from the above-mentioned substance P/NK-1 receptor system, caspases and the Bcl-2 family were thought to play a critical role in the growth inhibition in tumor cells, such as human promyelocytic leukemia HL-60 cells 3,28) and human breast adenocarcinoma MCF-7 cells. 29) In addition, cinobufacini, an extract from Calculus bovis, induced apoptosis in HepG2 cells through mitochondria-and caspasedependent pathways.…”

Section: Discussionmentioning

confidence: 99%

“…7) In addition, it was demonstrated that NK-1 receptor blockers could inhibit the growth of tumor cells. [9][10][11][12] Thus, we hypothesized that the substance P/NK-1 receptor system may be involved in both the analgesic and anticancer activities of LSW. In an attempt to explore this hypothesis, we measured the levels of substance P, the NK-1 receptor and other related factors in LSW-treated cancer cell lines and dorsal root ganglion (DRG) cells.…”

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Involvement of Substance P/Neurokinin-1 Receptor in the Analgesic and Anticancer Activities of Minimally Toxic Fraction from the Traditional Chinese Medicine Liu-Shen-Wan <i>in Vitro</i>

Jia

et al. 2014

Biological & Pharmaceutical Bulletin

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Liu-Shen-Wan (LSW), an ancient preparation used to treat localized infection with pain, was recently reported to possess anticancer activity. The mechanism responsible for LSW's analgesic and anticancer activity is unclear. In the present study, we obtained a LSW supernatant (LSWS) fraction from ultrasoundassisted ethanol extraction (yield 15.9%) which proved to be safer than LSW in terms of hepatotoxicity. The LSWS (1 and 10 µg/mL) exhibited a potent inhibitory effect on the bradykinin-evoked rapid release of substance P from dorsal root ganglion (DRG) cells. At concentrations of 0.1 µg/mL and higher, the LSWS resulted in a concentration-related growth inhibitory effect on HepG2, a representative cancer cell lines. The LSWS significantly down-regulated the neurokinin-1 (NK-1) receptor expression in both HepG2 and bradykinin-treated DRG cells. In addition to the NK-1 receptor-dependent growth inhibition in HepG2 cells (0.1-100 µg/mL), the LSWS induced mitochondria-mediated apoptosis at a higher concentration (1-100 µg/mL). In conclusion, we recently isolated a safer LSW fraction which maintained its analgesic and anticancer activity, and found that the substance P/NK-1 receptor system was partly responsible for these effects. Our findings will be useful for developing more effective and less toxic LSW preparations.Key words Liu-Shen-Wan; anticancer; analgesic; substance P; neurokinin-1 receptor Liu-Shen-Wan (LSW), a well-known heat clearing and detoxifying herbal preparation, is mainly composed of Calculus Bovis Cowherb Seed, Margarita Pecazine, Venenum Bufonis Toborinone, Broneolum Syntheticum Boro-Scopol, Moschus Muskone, and Realgar Reapam. This ancient prescription is effective for treating localized infections and inflammationassociated pain.1) LSW's analgesic effect has been known and used for more than 200 years.2) During the past 200 years, many other applications have been uncovered, including its use for the treatment of diphtheria, scarlet fever, pharyngotonsillitis, acute tonsillitis, purulent parotitis, encephalitis B and viral pneumonia.3) It was also recently reported that LSW had a potential anticancer activity. 2,3)Despite its approval by the China Food and Drug Administration and its use for nearly 200 years, traditional LSW is associated with some toxicity because it contains realgar and Venenum Bufonis, 4) both of which were found to be toxic if administered alone.5) This toxicity made LSW unacceptable to the international community as a therapeutic agent.6) In the present study, we isolated an ethanol fraction of LSW which maintained its analgesic and anticancer activities, but with a decreased level of toxicity. However, to the best of our knowledge, the mechanism(s) underlying LSW's analgesic and anticancer activity are still unclear.Because LSW has both analgesic and anticancer activities, we suppose that there might be some common mechanisms underlying these two activities. Substance P and its endogenous receptor, the neurokinin-1 (NK-1) receptor, 7) which play important roles in both pa...

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Neuropeptides in Cancer: Friend and Foe?

Berisha

Borniger

2022

Advanced Biology

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highly dynamic network of various cell types (e.g., cancer cells, endothelial cells, immune cells, fibroblasts) that exert differential effects on neuronal activity within the local environment. Thus, complex signaling between cancer and stromal cells in the TME results in altered firing rates of local nerves. Reciprocally, increased neuronal activity and subsequent release of classical neurotransmitters and/or neuropeptides within the TME results in enhanced cancer progression and subsequent metastasis in various preclinical models and clinical studies. [5][6][7][8][9] Nerves interact with multiple stromal cells in the TME where they indirectly promote tumor growth, progression, and subsequent metastasis. [10] Several studies have demonstrated that sympathetic nerve innervation and subsequent release of the neurotransmitter norepinephrine (NE) is increased in breast tumors. [6,8,9] However, recent work has demonstrated that there is an inverse relationship between tumor weight and norepinephrine content (i.e., larger the size of the tumor, the lower the levels of NE), despite increased innervation of sympathetic nerves within the TME. [11] These findings may be attributed to a relatively unexplored phenomenon: neuropeptide release within the TME. Neuropeptides are molecular messengers that regulate a variety of functions in the central and peripheral nervous systems via binding G-protein-coupled receptors (GPCRs) on target cells. One of the many functions of neuropeptides is serving as growth factors for normal cells via the activation of the heterotrimeric G protein Gq and subsequent synthesis of second messengers and engagement of tyrosine phosphorylation cascades. Neuropeptides act as neuromodulators, in that they can alter the response of neurons to neurotransmitters and other circulating signals, such as leptin, ghrelin, glucose, and insulin-all of which are affected during cancer progression. [12][13][14][15][16][17] For example, both neuropeptide Y (NPY) and hypocretin/orexin neurons appear to mediate some of the orexigenic effects of centrally administered ghrelin as administration of NPY receptor antagonists attenuated ghrelininduced feeding. Similarly, ghrelin-induced feeding was suppressed in orexin knockout mice, indicating that ghrelin may stimulate feeding through both the orexin and NPY systems. [18] However, neuropeptide signaling is exploited within cancer cells and many studies demonstrate the contribution of neuropeptides in tumor cell proliferation and migration, [19] with many major neuropeptides also potentially contributing to cancer processes (see Table 1). Additionally, neuropeptides exert direct Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptid...

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The substance P/neurokinin-1 receptor system in lung cancer: Focus on the antitumor action of neurokinin-1 receptor antagonists

Cited by 67 publications

References 30 publications

Involvement of substance P and the NK-1 receptor in human pathology

Involvement of substance P and the NK-1 receptor in human pathology

Involvement of Substance P/Neurokinin-1 Receptor in the Analgesic and Anticancer Activities of Minimally Toxic Fraction from the Traditional Chinese Medicine Liu-Shen-Wan <i>in Vitro</i>

Neuropeptides in Cancer: Friend and Foe?

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