title: IDO Downregulation Induces Sensitivity to Pemetrexed, Gemcitabine, FK866, and Methoxyamine in Human Cancer Cells.
abstract: Indoleamine 2,3-dioxygenase-1 (IDO) is an immune regulatory enzyme expressed by most human tumors. IDO levels in tumor cells correlate with increased metastasis and poor patient outcome and IDO is linked to tumor cell resistance to immunotherapy, radiation therapy, and chemotherapy. Knowledge of tumor cell-autonomous effects of IDO, independent of its well-known role in regulating and suppressing anti-tumor immune responses, is limited. Clonal populations of A549 human lung adenocarcinoma cells stably transfected with anti-IDO shRNA or scrambled control shRNA were used to study IDO effects on drug sensitivity and resistance. IFNγ was used to induce IDO in those cells. We show, for the first time, that IDO mediates human tumor cell resistance to the candidate anticancer drugs FK866 (an NAD+ inhibitor), methoxyamine (MX, a base excision repair [BER] inhibitor) and approved anticancer drugs pemetrexed (a folate anti-metabolite) and gemcitabine (a nucleoside analogue), and combined treatment with pemetrexed and MX, in the absence of immune cells. Concurrent knockdown of IDO and thymidylate synthase (TS, a key rate-limiting enzyme in DNA synthesis and repair) sensitizes human lung cancer cells to pemetrexed and 5FUdR to a greater degree than knockdown of either target alone. We conclude that BER in IDO-expressing A549 cells plays a major role in mediating resistance to a range of approved and candidate anticancer drugs. IDO inhibitors are undergoing clinical trials primarily to improve antitumor immune responses. We show that targeting IDO alone or in combination with TS is a potentially valuable therapeutic strategy for cancer treatment, independent of immune activity and in combination with conventional chemotherapy.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Saman
authors.initials: S
authors.lastname: Maleki Vareki
authors.affiliation: Department of Pathology, Western University, London, Ontario, Canada.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Di Cresce
authors.affiliation: Department of Oncology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ferguson
authors.affiliation: Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Rene
authors.initials: R
authors.lastname: Figueredo
authors.affiliation: Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Rytelewski
authors.affiliation: Department of Oncology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Department of Pathology, Western University, London, Ontario, Canada.
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
authors.affiliation: Department of Pathology, Western University, London, Ontario, Canada.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.|Department of Pathology, Western University, London, Ontario, Canada.|Department of Oncology, Western University, London, Ontario, Canada.|Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.|Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Koropatnick
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002999:Clone Cells; D004260:DNA Repair / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005467:Floxuridine / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D016513:Mice, SCID; D009243:NAD / Q000378:metabolism; D000068437:Pemetrexed / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000178:Acrylamides; D024682:BRCA2 Protein; D006898:Hydroxylamines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D034741:RNA, Small Interfering; D005467:Floxuridine; D000068437:Pemetrexed; D009243:NAD; D003841:Deoxycytidine; C005214:methoxyamine; D013940:Thymidylate Synthase; D000093542:Gemcitabine