Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach

Muñoz, Miguel; Coveñas, Rafael

doi:10.4103/1319-3767.187601

Cited by 26 publications

(18 citation statements)

References 43 publications

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“…In addition to their role as neurotransmitters, tachykinins and their receptors have been shown to strongly enhance cancer cell growth [34]. Particularly well studied is the tumorigenic role of the SP/NK1R complex in several cancer lines (for review see Muñoz and Coveñas [11, 12, 35, 36]). Moreover, overexpression of the NK1R has been observed in many cancer cell lines [37–39] in both of its isoforms.…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

Gutiérrez

Boada

2018

Cancer Cell Int

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BackgroundMetastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggressiveness although the underlying mechanisms are yet to be stablished.MethodsThe in vitro dose dependent effect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231LUC+ were assessed by wound healing and collagen-based cell invasion assays, respectively. The effect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular-weight kininogen) release to the cell culture supernatant of MDA-MB-231LUC+, were measured using western-blot analysis and an ELISA assay, respectively. Statistical significance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate.ResultsOur data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a model of metastatic cancer to bone (MDA-MB-231LUC+) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells. Finally, we demonstrate that NPs also trigger the acute release of HMWK (Bradykinin precursor) by MDA-MB-231LUC+, a molecule with both tumorigenic and pro-nociceptive activity.ConclusionsBased on these observations we conclude that NPs exposure modulates this breast cancer cellular line aggressiveness by increasing its ability to migrate and invade new tissues. Furthermore, these results also support the pro nociceptive and cancer promoter role of the peripheral nervous system, during the initial stages of the disease.

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Section: Discussionmentioning

confidence: 99%

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

Gutiérrez

Boada

2018

Cancer Cell Int

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“…In tumor cells, SP through the NK-1R promotes an anti-apoptotic effect as well as proliferation, migration, invasion and metastasis ( Figure 1) [13,25,27,30,36,37]. Cancer cells express both SP and the NK-1R, and it seems that the undecapeptide is involved in an autocrine mechanism that promotes mitogenesis in tumor cells [13,21,28,[38][39][40][41][42][43][44]. Cancer cell proliferation is activated via mitogen-activated protein kinases (MAPKs, including signal-regulated kinases 1 and 2 as well as p38MAPK) and then the expression of c-myc/c-fos is induced [25]; in these processes, the involvement of protein kinase C delta and Scr has been demonstrated ( Figure 1) [45].…”

Section: The Sp/nk-1r System and Cancer: Cell Signaling Pathways Ovementioning

confidence: 99%

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

Muñoz

Coveñas

2020

JCM

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Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca++ overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells. Thus, the SP/NK-1R system is involved in AML, and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is updated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (>20 mg/kg/day) for a period of time according to the response to treatment is suggested). Aprepitant is currently used in clinical practice as an anti-nausea medication.

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“…Second, hybridization of opioid agonist and NK1R antagonist pharmacophores produces analgesic molecules with reduced tolerance and side-effects (Largent-Milnes et al 2010). Third, NK1R antagonists have been shown to have anticancer activity in vitro and in vivo (Harford-Wright et al 2013;Garnier et al 2015;Muñoz and Coveñas 2016).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020

Matalińska

Lipiński

Kotlarz

et al. 2020

Int J Pept Res Ther

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In the present contribution we report design, synthesis and evaluation of receptor affinity, analgesic activity and cytotoxicity of a hybrid peptide, AWL3020. The peptide includes two pharmacophores, one of δ-opioid receptor (δOR) agonists and one of neurokinin-1 receptor (NK1R) antagonists. The design was motivated by the desire to obtain a compound with strong analgesic action and potential additional antiproliferative action. The compound displays high δOR affinity (IC 50 = 29.5 nM). On the other hand, it has only poor affinity for the NK1R (IC 50 = 70.28 μM). The substance shows good analgesic action which is however weaker than that of morphine. Regarding the effect on proliferation, the compound exhibits no pro-proliferative action in the assayed range. In higher concentrations, it has also cytotoxic activity. This effect is however not selective. The strongest effect of AWL3020 was found for melanoma MeW164 cell line (EC 50 = 46.27 μM in reduction of cell numbers after a few days of incubation; EC 50 = 37.78 μM in MTT assay).

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Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach

Cited by 26 publications

References 43 publications

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020

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