Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects
Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects
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环硫化合物靶向巨噬细胞极化成 M2/原肿瘤表型及其抗肿瘤作用
DOI：
10.1007/s00262-021-03085-1
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Komohara Yoshihiro
中科院分区：
文献类型：
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作者：
Pan Cheng;Fujiwara Yukio;Horlad Hasita;Iriki Toyohisa;Shiraishi Daisuke;Komohara Yoshihiro
肿瘤相关巨噬细胞（TAM），特别是M2样表型，促进肿瘤进展，使其成为抗肿瘤治疗的候选靶点。我们以前发现了一种环状硫化合物，洋葱素A（ONA），它通过抑制TAM的M2极化来抑制肿瘤进展。在本研究中，我们试图找到新的候选化合物具有更强的效果相比，ONA通过探索化合物的结构类似的ONA在几个环硫化合物。共筛选了81种环硫化合物，并使用人单核细胞衍生的巨噬细胞（HMDM）测试了它们对巨噬细胞向M2样表型极化的影响。在荷瘤小鼠模型中检查所鉴定的候选化合物的抗肿瘤作用。三种候选化合物抑制IL-10和肿瘤培养上清液（TCS）诱导的HMDM的M2极化。这些化合物还抑制由IL-10和TCS刺激的HMDM中的STAT 3活化，而这些化合物对肿瘤细胞中的STAT 3活化没有影响。此外，这些化合物在与HMDM共培养条件下抑制肿瘤细胞增殖，表明三种候选化合物通过调节肿瘤细胞和巨噬细胞之间的细胞-细胞相互作用来抑制肿瘤增殖。此外，这些候选化合物中的两种在LM 8荷瘤小鼠模型中对肿瘤生长和肺转移具有抑制作用。我们的研究确定了用于靶向TAM的M2极化的抗肿瘤治疗的新的候选环状硫化合物。
Tumor-associated macrophages (TAMs), especially the M2-like phenotype, promote tumor progression, making them candidate targets for anti-tumor therapy. We previously discovered a cyclic sulfur compound, Onionin A (ONA), which suppresses tumor progression by inhibiting the M2-polarization of TAMs. In the present study, we sought to find new candidate compounds possessing a stronger effect compared to ONA by exploring compounds with structures similar to those of ONA among several cyclic sulfur compounds. A total of 81 cyclic sulfur compounds were screened, and their effects on macrophage polarization toward an M2-like phenotype were tested using human monocyte-derived macrophages (HMDMs). The anti-tumor effects of the identified candidate compounds were examined in a tumor-bearing mouse model. Three candidate compounds inhibited both IL-10- and tumor culture supernatant (TCS)-induced M2-polarization of HMDMs. These compounds also suppressed STAT3 activation in HMDMs stimulated by IL-10 and TCS, whereas these compounds had no effect on STAT3 activation in tumor cells. Furthermore, these compounds inhibited tumor cell proliferation under co-culture conditions with HMDMs, indicating that the three candidate compounds suppress tumor proliferation by regulating cell–cell interactions between tumor cells and macrophages. In addition, two of these candidate compounds had inhibitory effects on tumor growth and lung metastasis in the LM8 tumor-bearing mouse model. Our study identified new candidate cyclic sulfur compounds for anti-tumor therapy targeting the M2-polarization of TAMs.