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首页> 外文期刊>Journal of dermatological science >Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells
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Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells

机译：HDAC抑制剂MS-275和IL-2的组合通过激活的细胞毒性T细胞在黑色素瘤模型中增强了抗肿瘤作用

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Background: Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma. Objective: The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model. Methods: B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents. Results: MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells. Conclusions: These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.
机译：背景：组蛋白脱乙酰基酶（HDAC）抑制剂具有免疫调节作用，在包括恶性黑色素瘤在内的多种肿瘤模型中均显示出抗肿瘤活性。目的：本研究探讨了IL-2和HDAC抑制剂MS-275联合治疗在小鼠黑素瘤模型中的有效性。方法：将B16F10细胞皮下植入C57BL / 6小鼠中，随机分为四组，分别通过皮下注射IL-2，经口管饲MS-275（每周5天/周，每天2周）或经C-BL7处理。两种药剂的结合。结果：MS-275治疗在结肠发生试验中显示出对B16细胞的剂量依赖性抑制作用。流式细胞仪分析表明，MS-275在体外诱导G1阻滞但不诱导细胞凋亡，但IL-2不能抑制细胞增殖。 MS-275和IL-2的组合在体内对黑素瘤肿瘤的重量和体积具有统计学上显着的累加抑制作用。与对照组或单药组相比，联合组的存活率明显更高。与在有瘤小鼠中进行MS-275治疗和未治疗组相比，联合疗法在淋巴结中产生的CD8 + CD69 + T细胞比例更高。用MS-275和联合疗法治疗的小鼠脾细胞在体外表现出比用IL-2治疗或未经治疗的小鼠脾细胞更大的黑色素瘤细胞裂解。在激活的CD8 + T细胞数量增加的情况下，可以看到IL-2和MS-275联合疗法在体内具有显着的抗肿瘤作用。结论：这些数据为考虑表观遗传学在恶性黑色素瘤未来治疗中的作用提供了令人信服的理由。

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