It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-κB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis.
AggarwalBBGehlotP (2009) Inflammation and cancer: how friendly is the relationship for cancer patients?Current Opinion in Pharmacology9: 351–369.
2.
AgrawalSSSaraswatiSMathurRPandeyM (2011) Anti-tumor properties of Boswellic acid against Ehrlich ascites cell-bearing mouse. Food and Chemical Toxicology49: 1924–1934.
3.
AlexanderJPKudohSMelsopKAHamiltonTAEdingerMGTubbsRR. (1993) T-Cells infiltrating renal cell carcinoma display a poor proliferative response though they can produce IL-2 and express IL-2 receptors. Cancer Research53: 1380–1387.
4.
AshikawaKShishodiaSFoktIPriebeWAggarwalBB (2004) Evidence that activation of NF-κB is essential for the cytotoxic effects of doxorubicin and its analogues. Biochemical Pharmacology67: 353–364.
5.
AwaraWMEl-SisiAEEl-SayadMEGodaAE (2004) The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumor: Does celecoxib enhance the anti-tumor activity of doxorubicin?Pharmacological Research50: 487–498.
6.
BasuSDasguptaPSChowdhuryJR (1995) Enhanced tumor growth in brain dopa-mine-depleted mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treat-ment. Journal of Neuroimmunology60: 1–8.
7.
BhattacharyyaSMd Sakib HossainDMohantySSankar SenGChattopadhyaySBanerjeeS. (2010) Curcumin reverses T-cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cellular and Molecular Immunology7: 306–315.
8.
BingisserRMTilbrookPAHoltPGKeesUR (1998) Macrophage-derived nitric oxide regulates T-cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. Journal of Immunology160: 5729–5734.
9.
CarvalhoGFabreCBraunTGrosjeanJAdesLAgouF. (2007) Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene26: 2299–2307.
ColleyDGToddCWLewisFAGoodgameRW (1979) Immune responses during human schistosomiasis mansoni, in vitro non-specific suppression of phytohemagglutinin responsiveness induced by exposure to certain schistosomal preparations. Journal of Immunology122: 1447–1453.
12.
DannaEASinhaPGilbertMClementsVKPulaskiBAOstrand-RosenbergS (2004) Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Research64: 2205–2211.
13.
DasTSaGPaszkiewicz-KozikEHilstonCMoltoLRaymanP. (2008) Renal cell carcinoma tumors induce T-cell apoptosis through receptor-dependent and receptor-independent pathways. Journal of Immunology180: 4687–4696.
14.
DoroshowJH (1986) The role of hydrogen peroxide and hydroxyl formation in the killing of Ehrlich tumor cells by anti-cancer quinine. Proceedings of the National Academy of Sciences of the United States of America83: 4514–4518.
15.
EckertRGrunerSVolkHDGieseCvon BaehrR (1989) Studies on the immunomodulatory effects of anthracycline antibiotics in mice: effects on immune responses and graft immunogenicity. Immunobiology179: 445–455.
16.
El-SwefySHassanenSI (2009) Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats. Annals of Hepatology8: 41–49.
17.
ElseaCRRobertsDADrukerBJWoodLJ (2008) Inhibition of p38 MAPK suppresses inflammatory cytokine induction by etoposide, 5-fluorouracil, and doxorubicin without affecting tumoricidal activity. PLoS One3: e2355.
18.
FerraroCQuemeneurLPrigentAFTaverneCRevillardJPBonnefoy-BerardN (2000) Anthracyclines trigger apoptosis of both G0-G1 and cycling peripheral blood lymphocytes and induce massive deletion of mature T- and B-cells. Cancer Research60: 1901–1907.
19.
FigueroaDJBreyerRMDefoeSKKargmanSDaughertyBLWaldburgerK. (2001) Expression of the cysteinyl leukotriene-1 receptor in normal human lung and peripheral blood leukocytes. American Journal of Respiratory and Critical Care Medicine163: 226–233.
20.
FornasieroMCFerrariMGnocchiPTrizioDIsettaAM (1992) Immunodepressive activity of FCE 23762 on humoral and cell-mediated immune responses in normal mice: comparison with doxorubicin. Agents Actions37: 311–318.
21.
FridlenderZGAlbeldaSM (2012) Tumor-associated neutrophils: friend or foe?Carcinogenesis33: 949–955.
22.
FroidevauxSLoorF (1994) Myeloid and lymphoid cell alterations in normal mice exposed to chemotherapy with doxorubicin and/or the multidrug-resistance reversing agent SDZ PSC 833. International Journal of Cancer59: 133–140.
23.
FunderudSNustadKLeaTVartdalFGaudernackGStenstadP. (1987) Fractionation of lymphocytes by immunomagnetic beads. In: KlausGG (ed) Lymphocytes: Practical Approach. Oxford, UK: IRL Press, pp. 55–65.
24.
GebhardBGnantMSchutzGRokaSWeigelGKandiolerD. (2000) Different transendothelial migration behavior pattern of blood monocytes derived from patients with benign and malignant diseases of the breast. Anticancer Research20: 4599–4604.
25.
GeorgeSKRajeshRKumarSSSulekhaBBalaramP (2008) A polyherbal ayurvedic drug—Indukantha Ghritha as an adjuvant to cancer chemotherapy via immunomodulation. Immunobiology213: 641–649.
26.
Gomes NdeMRezende CdeMFontesSPHovellAMLandgrafRGMatheusME. (2008) Anti-neoplastic activity of Copaifera multijuga oil and fractions against ascitic and solid Ehrlich tumor. Journal of Ethnopharmacology119: 179–184.
27.
KandilABazarbashiSMouradWA (2001) The correlation of Epstein–Barr virus expression and lymphocyte subsets with the clinical presentation of nodular sclerosing Hodgkin disease. Cancer91: 1957–1963.
28.
LamoureuxJStankovaJRola-PleszczynskiM (2006) Leukotriene D4 enhances immu-noglobulin production in CD40-activated human B-lymphocytes. Journal of Allergy and Clinical Immunology117: 924–930.
29.
LärfarsGLantoineFDevynckMAPalmbladJGyllenhammarH (1999) Activation of nitric oxide release and oxidative metabolism by leukotrienes B4, C4, and D4 in human polymorphonuclear leukocytes. Blood93: 1399–1405.
30.
MacfarlaneDEManzelLKriegAM (1997) Unmethylated CpG-containing oligo-deoxynucleotides inhibit apoptosis in WEHI 231 B-lymphocytes induced by several agents: evidence for blockade of apoptosis at a distal signaling step. Immunology91: 586–593.
31.
MarkertMAndrewsPCBabiorBM (1984) Measurement of O2- production by human neutrophils. The preparation and assay of NADPH oxidase-containing particles from human neutrophils. Methods in Enzymology105: 358–365.
32.
MatsuyamaMFunaoKHayamaTTanakaTKawahitoYSanoH. (2009) Relationship between cysteinyl leukotriene-1 receptor and human transitional cell carcinoma in bladder. Urology73: 916–921.
33.
MiJZhangXLiuYReddySKRabbaniZNSullengerBA. (2007) NF-κB inhibition by an adenovirus-expressed aptamer sensitizes TNFα-induced apoptosis. Biochemical and Biophysical Research Communications359: 475–480.
34.
MoserBWolfMWalzALoetscherP (2004) Chemokines: multiple levels of leuko-cyte migration control. Trends in Immunology25: 75–84.
35.
NorelXBrinkC (2004) The quest for new cysteinyl leukotriene and lipoxin receptors: recent clues. Pharmacology and Therapeutics103: 81–94.
36.
NyayapatiSAfshanGLornitzoFByrnesRWPeteringDH (1996) Depletion of cellular iron by BPS and ascorbate: effect on toxicity of adriamycin. Free Radical Biology and Medicine20: 319–329.
37.
OfferSShoseyovDBibiHElirazAMadarZ (2003) A leukotriene receptor antagonist modulates iNOS in the lung and in a leukotriene-free cell model. Nitric Oxide9: 10–17.
38.
OhmJECarboneDP (2002) Immune dysfunction in cancer patients. Oncology16: 11–18.
39.
OsmanAMSayed-AhmedMMKhayyalMTEl-MerzabaniMM (1993) Hyper-thermic potentiation of cisplatin on solid Ehrlich carcinoma. Tumori79: 268–272.
40.
PericleFKirkenRABronteVSconocchiaGDaSilvaLSegalDM (1997) Immunocompromised tumor-bearing mice show a selective loss of STAT5a/b expression in T- and B-lymphocytes. Journal of Immunology159: 2580–2585.
PilarskiLMAndrewsEJMantMJRuetherBA (1986) Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function. Journal of Clinical Immunology6: 491–501.
43.
PuvvadaSDFunkhouserWKGreeneKDealAChuHBaldwinAS. (2010) NF-κB and Bcl-3 activation are prognostic in metastatic colorectal cancer. Oncology78: 181–188.
44.
QueirozMLValadaresMCBincolettoCDieamantGC (2004) Ehrlich ascites tumor as a tool in the development of compounds with immunomodulatory properties. Immunopharmacology and Immunotoxicology26: 511–525.
45.
RigasBGoldmanILevineL (1993) Altered eicosanoid levels in human colon cancer. Journal of Laboratory and Clinical Medicine122: 518–523.
46.
RomanoMClariaJ (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB Journal17: 1986–1995.
47.
SadzukaYSugiyamaTSuzukiHSawanishiHMiyamotoK (2004) Increased effects of MPDAX, a novel xanthine derivative, on antitumor activity of doxorubicin. Toxicology Letters150: 341–349.
48.
Sayed-AhmedMMSalmanTMGaballahHEAbou El-NagaSANicolaiRCalvaniM (2001) Propionyl-L-carnitine as protector against adriamycin-induced cardio-myopathy. Pharmacological Research43: 513–520.
49.
SeguraJABarberoLGMarquezJ (2000) Ehrlich ascites tumor unbalances splenic cell populations and reduces responsiveness of T-cells to Staphylococcus aureus enterotoxin B stimulation. Immunology Letters74: 111–115.
50.
ShiFMacEwenEGKurzmanID (1993) In vitro and in vivo effect of doxorubicin combined with liposome-encapsulated muramyl tripeptide on canine monocyte activation. Cancer Research53: 3986–3991.
51.
SpinozziFRussanoAMPiattoniSAgeaEBistoniOde BenedictisD. (2004) Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T-lymphocytes. Clinical and Experimental Allergy34: 1876–1882.
52.
TimothyBHDavidAMPamelaAFGeorgeTR (1997) A cytotoxicity evaluation of anti-microbial and non-microbial wound cleansers. Derma Sciences5: 1–6.
53.
TribukaitBMobergerGZetterbergA (1975) Methodological aspects of rapid flow cytofluorometry for DNA analysis of human urinary bladder cells. In: GodheWSchumannJBucherTH (eds) Pulse-Cytophotometry, Part I. Ghent, Belgium: European press, Medicon, pp. 50–60.
54.
UjhazyPZaleskisGMihichEEhrkeMJBerlethES (2003) Doxorubicin induces specific immune functions and cytokine expression in peritoneal cells. Cancer Immunology, Immunotheraphy52: 463–472.
55.
van der VeenRCDietlinTAPenLGrayJDHofmanFM (2000) Antigen presentation to TH1 but not TH2 cells by macrophages results in nitric oxide production and inhibition of T-cell proliferation: IFNγ is essential but insufficient. Cellular Immunology206: 125–135.
56.
VindelovLL (1977) Flow micro-fluorometric analysis of nuclear DNA in cells from solid tumors and cell suspensions. Virchows Archiv (Cell Pathol.)24: 227–242.
57.
WenzelSE (1998) New approaches to anti-inflammatory therapy for asthma. American Journal of Medicine104: 287–300.
58.
YuanHSongJLiXLiNDaiJ (2006) Immunomodulation and anti-tumor activity of κ-carrageenan oligosaccharides. Cancer Letters243: 228–234.
59.
ZhuJQiuYSFigueroaDJBandiVGalczenskiHHamadaK. (2005) Localization and upregulation of cysteinyl leukotriene-1 receptor in asthmatic bronchial mucosa. American Journal of Respiratory Cell and Molecular Biology33: 531–540.
