Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects.
Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects.
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DOI：
10.1016/j.isci.2021.102673
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发表时间：
2021-06-25
期刊：
影响因子：
5.8
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
--
作者：
Cheng G;Hardy M;Topchyan P;Zander R;Volberding P;Cui W;Kalyanaraman B
羟基脲 (HU) 是 FDA 批准的用于治疗镰状细胞病的药物，可单独用作抗肿瘤药物，也可与传统化疗或放疗联合使用。 HU 主要用于治疗骨髓增生性疾病，因为它抑制参与 DNA 合成的核糖核苷酸还原酶。 HU 中的羟基被认为对其抗增殖和化疗作用至关重要。在这里，我们用连接有不同链长的烷基的三苯基鏻阳离子取代了 HU 中的羟基，形成了一类新的线粒体靶向 HU (Mito-HU)。延长烷基侧链长度可增加 Mito-HU 的疏水性、抑制氧化磷酸化以及肿瘤细胞的抗增殖作用。随着 Mito-HU 疏水性的增加，线粒体复合物 I 和复合物 III 诱导的耗氧量均减少。疏水性更强的 Mito-HU 还可以有效抑制单核细胞骨髓来源的抑制细胞和抑制性中性粒细胞，并刺激 T 细胞反应，这表明它们具有潜在的抗肿瘤免疫调节机制。 Mito-HU 靶向 OXPHOS 并在亚微摩尔水平抑制癌细胞增殖 疏水性更强的 Mito-HU 更有效地抑制线粒体呼吸 疏水性更强的 Mito-HU 可能抑制 MDSC 和中性粒细胞，激活 T 细胞 抑制作用的 IC50 在肿瘤细胞、MDSC 和中性粒细胞中相似；有机化学；生物科学；免疫学
Hydroxyurea (HU), an FDA-approved drug for treating sickle cell disease, is used as an antitumor drug alone and together with conventional chemotherapeutics or radiation therapy. HU is used primarily to treat myeloproliferative diseases because it inhibits the enzyme ribonucleotide reductase involved in DNA synthesis. The hydroxyl group in HU is considered critical for its antiproliferative and chemotherapeutic effects. Here, we substituted the hydroxyl group in HU with a triphenylphosphonium cation attached to an alkyl group with different chain lengths, forming a new class of mitochondria-targeted HU (Mito-HU). Elongating the alkyl side chain length increased the hydrophobicity of Mito-HUs, inhibition of oxidative phosphorylation, and antiproliferative effects in tumor cells. Both mitochondrial complex I- and complex III-induced oxygen consumption decreased with the increasing hydrophobicity of Mito-HUs. The more hydrophobic Mito-HUs also potently inhibited the monocytic myeloid-derived suppressor cells and suppressive neutrophils, and stimulated T cell response, implicating their potential antitumor immunomodulatory mechanism. Mito-HUs target OXPHOS & inhibit cancer cell proliferation at sub-micromolar levels More hydrophobic Mito-HUs more potently inhibit mitochondrial respiration More hydrophobic Mito-HUs may inhibit MDSCs & neutrophils, activate T cells The IC50s for inhibition are similar in tumor cells, MDSCs, and neutrophils Drugs; Organic chemistry; Biological sciences; Immunology
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影响因子：
4.8
作者：
Boyle, Kathleen A.;Van Wickle, Jonathan;Dwinell, Michael B.
通讯作者：
Dwinell, Michael B.
影响因子：
6.6
作者：
Langley, Monica;Ghosh, Anamitra;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
影响因子：
8.8
作者：
Benjamin, Don;Robay, Dimitri;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
10.1
作者：
Hossain, Fokhrul;Al-Khami, Amir A.;Ochoa, Augusto C.
通讯作者：
Ochoa, Augusto C.
DOI：
10.1073/pnas.1800695115
发表时间：
2018-10-02
影响因子：
11.1
作者：
Feng, Shan;Cheng, Xi;Lu, Xin
通讯作者：
Lu, Xin