title: The tryptophan derivative, tranilast, and conditioned medium with indoleamine 2,3-dioxygenase-expressing cells inhibit the proliferation of lymphoid malignancies.
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.
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Shihoko
authors.initials: S
authors.lastname: Suwa
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kasubata
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Miyu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014364:Tryptophan / Q000031:analogs & derivatives; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D017077:Culture Media, Conditioned; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D062367:ortho-Aminobenzoates; D014364:Tryptophan; C012293:tranilast