Paracrine and autocrine interactions in melanoma: histamine is a relevant player in local regulation

Falus, András; Hegyesi, Hargita; Lázár‐Molnár, Eszter; Pós, Zoltán; László, Valéria; Darvas, Zsuzsanna

doi:10.1016/s1471-4906(01)02050-6

Cited by 55 publications

(48 citation statements)

References 29 publications

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“…In addition, involvement of histamine in the molecular machinery of melanoma progression have been reported recently (25,26). The development of some allergic reactions, infection, and tumors are associated with excessive histamine production.…”

Section: Discussionmentioning

confidence: 96%

Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice

Koncz

Pásztói

Mazán

et al. 2007

The Journal of Immunology

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Histamine is a key regulator of the immune system. Several lines of evidence suggest the role of histamine in T cell activation and accelerated Th1 immune response is a hallmark of histidine decarboxylase knockout (HDC-KO) mice, with a complete lack of endogenously produced histamine. According to our previous work, T lymphocytes produce NO upon activation, and NO is necessary for effective T cell activation. To study the role of histamine in T cell activation, we investigated cytokine production and T cell signal transduction in HDC-KO and wild-type (WT) mice. In the absence of histamine, an elevated IFN-γ mRNA and protein levels of splenocytes (p < 0.001; p = 0.001, respectively) were associated with a markedly increased (2.5-fold, p = 0.0009) NO production, compared with WT animals. Furthermore, histamine treatment decreased the NO production of splenocytes from both WT and HDC-KO mice (p = 0.001; p = 0.0004, respectively). NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1,2-diolate-diethylenetriamine elicited IFN-γ production (p = 0.0002), whereas NO synthase inhibitors NG-monomethyl-l-arginine and nitronidazole both inhibited IFN-γ production (p = 0.002 and p = 0.01, respectively), suggesting the role of NO in regulating IFN-γ synthesis. Cytoplasmic Ca2+ concentration of unstimulated T cells was increased in the HDC-KO mice (p = 0.02), whereas T cell activation-induced δ Ca2+-signal was similar in both HDC-KO and WT animals. Our present data indicate that, in addition to its direct effects on T lymphocyte function, histamine regulates cytokine production and T cell signal transduction through regulating NO production.

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Section: Discussionmentioning

confidence: 96%

Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice

Koncz

Pásztói

Mazán

et al. 2007

The Journal of Immunology

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“…An alternative explanation would be that terfenadine and loratadine act on additional (undiscovered) HR or other molecular targets in neoplastic MC. Likewise, a number of previous and more recent data suggest that certain CYP450 isoenzymes serve as potential targets of terfenadine and loratadine and thus are mediating anti-neoplastic effects of these agents [22,[39][40][41][42][43]. If so, one could speculate that the other HR blockers tested did not interact with such enzymes in the same way or interact only with other CYP450 variants.…”

Section: Discussionmentioning

confidence: 96%

“…Another interesting concept is that histamine and histamine-metabolizing enzymes, both of which may interact with CYP450 isoenzymes, regulate the growth and survival of neoplastic cells in various tumors [39][40][41][42][43]. Some of these interactions may also point to autocrine or intercrine growth regulation in neoplastic cells [39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

“…Some of these interactions may also point to autocrine or intercrine growth regulation in neoplastic cells [39][40][41][42][43]. Since MC produce and contain considerable amounts of histamine it might be tempting to speculate that some of the HR blockers disrupt such autocrine or intercrine pathways involving histamine and histaminebinding molecules in neoplastic MC.…”

Section: Discussionmentioning

confidence: 99%

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H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells

Hadzijusufovic

Peter

Gleixner

et al. 2010

Experimental Hematology

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Objective-In mast cell (MC) neoplasms, clinical problems requiring therapy include i) the local aggressive and sometimes devastating growth of MC and ii) mediator-related symptoms. A key mediator of MC responsible for clinical symptoms is histamine. Therefore, the use of histamine receptor (HR) antagonists is an established approach to block histamine effects in these patients.Methods and Results-We screened for additional beneficial effects of HR antagonists and asked whether any of these agents would also exert growth-inhibitory effects on primary neoplastic MC, the human MC line HMC-1, and on two canine MC lines, C2 and NI-1. We found that the HR1 antagonists terfenadine and loratadine suppress spontaneous growth of HMC-1, C2, and NI-1 cells, as well as growth of primary neoplastic MC in all donors tested (human patients, n=5; canine patients, n=8). The effects of both drugs were found to be dose-dependent (IC 50 : terfenadine, 1-20 μM; loratadine, 10-50 μM). Both agents also produced apoptosis in neoplastic MC and augmented apoptosis-inducing effects of two KIT-targeting drugs, PKC412 and dasatinib. The other HR1 antagonists (fexofenadine, diphenhydramine) and HR2 antagonists (famotidine, cimetidine, ranitidine) tested did not exert substantial growth-inhibitory effects on neoplastic MC. None of the histamine receptor blockers were found to modulate cell cycle progression in neoplastic MC. Conclusions-The Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts (terfenadine) alone or in combination with KIT-inhibitors, can also affect in vivo neoplastic MC growth remains to be determined.

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“…The role of histamine in tumor development (14) has already been demonstrated and the involvement of histamine in colon tumor cell growth has also been established. Also this function was postulated in the multistage model of carcinogenesis in association with inflammatory responses (15).…”

Section: Cd25mentioning

confidence: 99%

Impact of Systemic Histamine Deficiency on the Crosstalk Between Mammary Adenocarcinoma and T Cells

Hegyesi¹,

Colombo

Pállinger³

et al. 2007

J Pharmacol Sci

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Abstract. The purpose of the present study was to investigate the influence of lack of histamine (HA) on tumor growth and functions of T cells in order further to illustrate the mechanism of immunological tolerance induction by HA. We assessed the phenotype and cytokine production of splenic lymphocytes in syngeneic HA-free (histidine decarboxylase knock-out) (HDC KO) and wild-type mice, inoculated subcutaneously with the LM2 murine breast cancer cell line. Relative quantification of target mRNA was performed with a TaqMan real-time RT-PCR assay. The CD4 + CD25high+ Treg cell numbers were significantly smaller in the tumor-bearing KO mice than in the wild type ones measured by flow-cytometry. The expression of forkhead box P3 (Foxp3) decreased significantly and the copies of splenic Tbox-21 (T-bet) transcriptional factor mRNA was higher in HDC KO tumor-bearing mice than those of normal mice. The cytokine levels showed that a smaller number of interleukin-13-producing Th2 cells were elicited compared to interferon-γ-producing Th1 cells in the tumor-bearing HDC KO mice. In conclusion, the present study demonstrates that endogenous histamine stimulates the growth of breast adenocarcinoma tumor implants in mice by suppressing anti-tumor immunity.

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Paracrine and autocrine interactions in melanoma: histamine is a relevant player in local regulation

Cited by 55 publications

References 29 publications

Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice

Nitric Oxide Mediates T Cell Cytokine Production and Signal Transduction in Histidine Decarboxylase Knockout Mice

H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells

Impact of Systemic Histamine Deficiency on the Crosstalk Between Mammary Adenocarcinoma and T Cells

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