The tryptophan derivative, tranilast, and conditioned medium with indoleamine 2,3-dioxygenase-expressing cells inhibit the proliferation of lymphoid malignancies

Suwa,Shihoko; Kasubata,Aya; Kato,Miyu; Iida,Megumi; Watanabe,Ken; Miura,Osamu; Fukuda,Tetsuya

doi:10.3892/ijo.2015.2825

The tryptophan derivative, tranilast, and conditioned medium with indoleamine 2,3-dioxygenase-expressing cells inhibit the proliferation of lymphoid malignancies

Authors:
- Shihoko Suwa
- Aya Kasubata
- Miyu Kato
- Megumi Iida
- Ken Watanabe
- Osamu Miura
- Tetsuya Fukuda
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Affiliations: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
Published online on: January 9, 2015 https://doi.org/10.3892/ijo.2015.2825
Pages: 1369-1376

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Abstract

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that catalyzes tryptophan degradation and induces immunosuppression. Although IDO is an important factor that allows tumors to escape from immunological attack, its effect on lymphoid malignancies has not been fully revealed. We evaluated the expression of IDO in samples from patients with B-cell malignancies. The IDO expression in the tumor samples was comparable to those in peripheral blood mononuclear cells from healthy donors and had mainly originated from non-B cell populations. We introduced IDO gene into Chinese hamster ovary (CHO) cells. We then cultured various cell lines using CHO- or CHO-IDO-conditioned medium. Compared with the CHO medium (CHO-CM), the CHO-IDO medium (IDO-CM) decreased the viability of lymphoid cell lines but not those of the non-lymphoid lines. Next, we examined the effects of tryptophan metabolites on lymphoid tumors, and revealed that the drug N-[3',4'-dimethoxycinnamoyl] anthranilic acid (tranilast), a synthetic derivative of the tryptophan metabolite, was able to repress proliferation and dose-dependently induce cell death of lymphoid cell lines. Tranilast induced the activation of the c-Jun N-terminal kinase, which is activated by cellular stress, in lymphoid cells. The effect of tranilast on lymphoid cells was independent of the aryl hydrocarbon receptor (AhR) although tranilast has been reported to be an AhR agonist. Finally, the administration of tranilast decreased murine lymphoid tumor progression in vivo. These results indicated that IDO and tryptophan derivatives, particularly tranilast, can be tools for the therapy for lymphoid malignancies.

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1	Fallarino F, Grohmann U, Vacca C, et al: T cell apoptosis by tryptophan catabolism. Cell Death Differ. 9:1069–1077. 2002. View Article : Google Scholar : PubMed/NCBI
2	Fallarino F, Grohmann U, You S, et al: The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 176:6752–6761. 2006. View Article : Google Scholar : PubMed/NCBI
3	Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U and Ferrara GB: Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 196:459–468. 2002. View Article : Google Scholar : PubMed/NCBI
4	Munn DH, Zhou M, Attwood JT, et al: Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 281:1191–1193. 1998. View Article : Google Scholar : PubMed/NCBI
5	Mellor AL, Sivakumar J, Chandler P, et al: Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol. 2:64–68. 2001. View Article : Google Scholar : PubMed/NCBI
6	Mellor AL and Munn DH: IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 4:762–774. 2004. View Article : Google Scholar : PubMed/NCBI
7	Inaba T, Ino K, Kajiyama H, et al: Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol Oncol. 115:185–192. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ino K, Yamamoto E, Shibata K, et al: Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res. 14:2310–2317. 2008. View Article : Google Scholar : PubMed/NCBI
9	Sharma MD, Baban B, Chandler P, et al: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest. 117:2570–2582. 2007. View Article : Google Scholar : PubMed/NCBI
10	Platten M, Ho PP, Youssef S, et al: Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 310:850–855. 2005. View Article : Google Scholar : PubMed/NCBI
11	Jasperson LK, Bucher C, Panoskaltsis-Mortari A, et al: Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Blood. 111:3257–3265. 2008. View Article : Google Scholar
12	Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Mellor AL, Munn DH and Blazar BR: Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood. 114:5062–5070. 2009. View Article : Google Scholar : PubMed/NCBI
13	Gupta S, Barrett T, Whitmarsh AJ, et al: Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15:2760–2770. 1996.PubMed/NCBI
14	Hu D and Kipps T: Reduction in mitochondrial membrane potential is an early event in Fas-independent CTL-mediated apoptosis. Cell Immunol. 195:43–52. 1999. View Article : Google Scholar : PubMed/NCBI
15	Tohda S, Nara N, Murohashi I and Aoki N: Establishment of an interleukin-3-dependent leukemic cell line from a patient with chronic lymphocytic leukemia in the acute phase. Blood. 78:1789–1794. 1991.PubMed/NCBI
16	Opitz CA, Litzenburger UM, Sahm F, et al: An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 478:197–203. 2011. View Article : Google Scholar : PubMed/NCBI
17	Nguyen NT, Kimura A, Nakahama T, et al: Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA. 107:19961–19966. 2010. View Article : Google Scholar : PubMed/NCBI
18	Prud’homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V and Jothy S: Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLoS One. 5:e138312010. View Article : Google Scholar
19	Maby-El Hajjami H, Amé-Thomas P, Pangault C, et al: Functional alteration of the lymphoma stromal cell niche by the cytokine context: role of indoleamine-2,3 dioxygenase. Cancer Res. 69:3228–3237. 2009. View Article : Google Scholar : PubMed/NCBI
20	Godin-Ethier J, Hanafi LA, Duvignaud JB, Leclerc D and Lapointe R: IDO expression by human B lymphocytes in response to T lymphocyte stimuli and TLR engagement is biologically inactive. Mol Immunol. 49:253–259. 2011. View Article : Google Scholar : PubMed/NCBI
21	Ninomiya S, Hara T, Tsurumi H, et al: Indoleamine 2,3-dioxy-genase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol. 90:409–416. 2011. View Article : Google Scholar
22	Rogosnitzky M, Danks R and Kardash E: Therapeutic potential of tranilast, an anti-allergy drug, in proliferative disorders. Anticancer Res. 32:2471–2478. 2012.PubMed/NCBI
23	Platten M, Eitel K, Wischhusen J, Dichgans J and Weller M: Involvement of protein kinase Cdelta and extracellular signal-regulated kinase-2 in the suppression of microglial inducible nitric oxide synthase expression by N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast). Biochem Pharmacol. 66:1263–1270. 2003. View Article : Google Scholar : PubMed/NCBI
24	Chikaraishi A, Hirahashi J, Takase O, et al: Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol. 427:151–158. 2001. View Article : Google Scholar : PubMed/NCBI
25	Johnson GL and Nakamura K: The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta. 1773:1341–1348. 2007. View Article : Google Scholar : PubMed/NCBI
26	Behrens A, Sibilia M and Wagner EF: Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet. 21:326–329. 1999. View Article : Google Scholar : PubMed/NCBI