通过多模态机制抑制吲哚胺 2,3 双加氧酶 1 增强放射治疗。
Enhancement of radiation therapy by indoleamine 2,3 dioxygenase 1 inhibition through multimodal mechanisms.
机构信息
Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
出版信息
BMC Cancer. 2023 Jan 18;23(1):62. doi: 10.1186/s12885-023-10539-5.
BACKGROUND
Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that converts tryptophan to kynurenine. IDO1 expression is found not only in tumor cells but also in immune cells and is associated with tumor proliferation and immune responses. IDO1 inhibitors and radiation may cooperatively suppress tumor proliferation through the alterations in the Wnt/β-catenin pathway, cell cycle, and immune response. We investigated the antitumor effects of combination therapy of an IDO1 inhibitor, 1-methyl tryptophan (1-MT), and radiation on colorectal cancer.
METHODS
In vitro experiments were conducted using human and murine colon cancer cell lines (HCT116, HT-29, and Colon26). Cell growth inhibition was assessed using a MTS assay and Clonogenic assay. Cells were cultured for 48 h with or without 500 µM 1-MT after exposure to radiation (4 Gy). Cell cycle effects and modulation of Wnt/β-catenin pathway were evaluated using western blot analysis, flow cytometry, RT-PCR. Subcutaneous Colon26 tumors in BALB/c mice were treated by oral 1-MT (6 mg/mL) for 2 weeks and/or local radiation (10 Gy/10 fr). Bromodeoxyuridine (BrdU) incorporation in tumor cells and expression of differentiation markers of immune cells were evaluated using immunohistochemistry.
RESULTS
1-MT and a small interfering RNA against IDO1 suppressed proliferation of all cell lines, which was rescued by kynurenine. Clonogenic assay showed that administration of 1-MT improved radiosensitivity by suppressing the Wnt/β-catenin pathway activated by radiation and enhancing cell cycle arrest induced by radiation. Combination therapy showed a further reduction in tumor burden compared with monotherapies or untreated control, inducing the highest numbers of intratumoral CD3 + and CD8 + T cells and the lowest numbers of Foxp3 + and BrdU-positive tumor cells.
CONCLUSIONS
The combination of 1-MT and radiation suppressed colon cancer cells in vitro and in vivo via multiple mechanisms.
背景
吲哚胺 2,3-双加氧酶 1（IDO1）是一种将色氨酸转化为犬尿氨酸的酶。IDO1 的表达不仅存在于肿瘤细胞中，也存在于免疫细胞中，与肿瘤增殖和免疫反应有关。IDO1 抑制剂和辐射可能通过改变 Wnt/β-连环蛋白通路、细胞周期和免疫反应来协同抑制肿瘤增殖。我们研究了 IDO1 抑制剂 1-甲基色氨酸（1-MT）与辐射联合治疗对结直肠癌的抗肿瘤作用。
方法
使用人源和鼠源结肠癌细胞系（HCT116、HT-29 和 Colon26）进行体外实验。使用 MTS 测定法和集落形成测定法评估细胞生长抑制。在暴露于辐射（4 Gy）后，将细胞在有无 500 µM 1-MT 的情况下培养 48 小时。通过 Western blot 分析、流式细胞术、RT-PCR 评估细胞周期效应和 Wnt/β-连环蛋白通路的调节。通过口服 1-MT（6 mg/mL）治疗 2 周和/或局部辐射（10 Gy/10 次）治疗 BALB/c 小鼠皮下 Colon26 肿瘤。使用免疫组织化学评估肿瘤细胞中 BrdU 掺入和免疫细胞分化标志物的表达。
结果
1-MT 和针对 IDO1 的小干扰 RNA 抑制了所有细胞系的增殖，而色氨酸可挽救该增殖作用。集落形成测定法表明，1-MT 的给药通过抑制辐射激活的 Wnt/β-连环蛋白通路并增强辐射诱导的细胞周期阻滞，提高了放射敏感性。与单独治疗或未治疗的对照组相比，联合治疗进一步降低了肿瘤负担，诱导了最多数量的肿瘤内 CD3+和 CD8+T 细胞，以及最低数量的 Foxp3+和 BrdU 阳性肿瘤细胞。
结论
1-MT 和辐射的联合治疗通过多种机制在体外和体内抑制结肠癌细胞。
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