DCK confers sensitivity of DCTD-positive cancer cells to oxidized methylcytidines.
DCK confers sensitivity of DCTD-positive cancer cells to oxidized methylcytidines.
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DCK 赋予 DCTD 阳性癌细胞对氧化甲基胞苷的敏感性
DOI：
10.1093/procel/pwac028
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发表时间：
2023-06-28
期刊：
影响因子：
21.1
通讯作者：
Zhou, Dan
中科院分区：
文献类型：
--
作者：
Zhao, Ya-Hui;Jiang, Wei;Gao, Hai;Pang, Guo-Zheng;Wu, Yu-Shuang;Wang, Yuan-Xian;Sheng, Meng-Yao;Xie, Jia-Ying;Wu, Wan-Ling;Ji, Zhi-Jian;Du, Ya-Rui;Zhang, Lei;Wang, Xiao-Qin;Walsh, Colum P.;Jiang, Hai;Xu, Guo-Liang;Zhou, Dan
胞苷类似物，如地西他滨（DAC）和阿糖胞苷（ara-C），已广泛用于多种癌症的临床治疗，包括骨髓增生异常综合征和急性髓性白血病（AML; Appelbaum et al. 1999; Saba 2007）。然而，耐药性导致治疗失败和疾病复发是一个尚未解决的问题。某些癌细胞依靠挽救酶胞苷脱氨酶（CDA）和dCMP脱氨酶（DCTD）来脱氨灭活这些胞苷衍生物药物（Jamieson et al. 1987; Ebrahem et al. 2012）。开发新的化疗核苷类药物来克服细胞脱胺活性增加所引起的耐药是势在必行的。氧化甲基胞苷5-羟甲基-2 α脱氧胞苷（5hmdC）和5-甲氧基-2 α脱氧胞苷（5fdC）已成为一类新的有前途的抗癌化疗药物，特别是在上述情况下（Zauri等，2015）。研究发现，它们通过cda定向脱胺作用发挥肿瘤杀伤作用，产生尿嘧啶衍生物5hmdU和5fdU，可被纳入基因组DNA，导致广泛的DNA损伤和随后的细胞周期阻滞和细胞死亡（Zauri et al. 2015）。5hmdC和5fdC脱胺衍生物的有害影响在癌症细胞中呈现出一种新的脆弱性，这些细胞对常用的胞苷类似物具有cda驱动的化学耐药。然而，CDA的高表达仅在少数癌症类型中发现（Zauri et al. 2015），这可能限制了5hmdC和5fdC在癌症治疗中的应用。我们认为，分析5hmdC和5fdC对不同遗传背景的不同癌细胞的杀伤作用，有助于我们发现新的代谢途径，扩大5hmdC和5fdC的治疗潜力。我们分析了45种人类癌细胞株中5hmdC和5fdC的半数最大抑制浓度（IC50）（表S1）。结果表明，10株细胞株对5hmdC敏感，19株细胞株对5fdC敏感（IC50< 50 μmol/L）。通过分析这些细胞系中CDA的mRNA水平，我们发现CDA仅在2个5hmdc敏感细胞系和14个5fdc敏感细胞系中表达。有趣的是，一些缺乏CDA表达的细胞系，包括SEM（人类急性淋巴母细胞白血病细胞系）和Raji（人类B淋巴母细胞样细胞系），被氧化甲基胞苷或两者强烈抑制（图1A和表S1），这表明存在不依赖CDA的代谢途径，指导5hmdC和5fdC的细胞毒性。我们通过在培养基中添加10 μmol/L的5hmdC或5fdC，对SEM、Raji和MDA-MB-231的增殖进行了分析，发现5hmdC或5fdC显著抑制SEM和Raji细胞株的增殖（图1B），并且这两种细胞株对5hmdC、5fdC或两者的敏感性远高于表达CDA的MDA-MB-231（图1A）。5hmdC和5fdC处理的SEM和Raji细胞显示出增加的γ - h2ax信号（图1C），表明5hmdC和5fdC能够在没有cda定向脱胺的情况下诱导DNA损伤。5hmdC处理24小时导致SEM细胞的s期阻滞（图S1A和S1B）和凋亡增加（图S1C和S1D）。综上所述，这些数据表明我们已经确定了一组能够通过不依赖于cda的途径代谢氧化甲基胞苷的癌细胞。由于胞苷单磷酸激酶1 （CMPK1）不能磷酸化修饰的胞苷单磷酸，5mdC、5hmdC和5fdC直接掺入…
Cytidine analogs, such as decitabine (DAC) and cytarabine (ara-C), have been widely used in the clinical treatment for several cancer types, including myelodysplastic syndrome and acute myeloid leukemia (AML; Appelbaum et al. 1999; Saba 2007). However, drug resistance causing treatment failure and disease relapse is an unresolved problem to date. Certain cancer cells rely on the salvage enzymes cytidine deaminase (CDA) and dCMP deaminase (DCTD) to inactivate these cytidine derivative drugs by deamination (Jamieson et al. 1987; Ebrahem et al. 2012). It is imperative to develop new categories of chemotherapeutic nucleosides to overcome the drug resistance caused by such increased cellular deamination activity. The oxidized methylcytidines 5-hydroxymethyl-2ʹdeoxycytidine (5hmdC) and 5-formy-2ʹdeoxycytidine (5fdC) have emerged as a new class of promising anticancer chemotherapeutic agents, especially for the above settings (Zauri et al. 2015). They were found to exert tumor-killing effect through CDA-directed deamination, which produces uridine derivatives 5hmdU and 5fdU that can be incorporated into genomic DNA, resulting in extensive DNA damage and subsequent cell cycle arrest and cell death (Zauri et al. 2015). The detrimental effects of deaminated derivatives of 5hmdC and 5fdC present a novel vulnerability in cancer cells bearing CDA-driven chemoresistance against the commonly used cytidine analogs. Nevertheless, high CDA expression is only found in a few cancer types (Zauri et al. 2015), which could limit the application of 5hmdC and 5fdC in cancer treatment. We reasoned that profiling the killing effects of 5hmdC and 5fdC on different cancer cells with various genetic backgrounds could help us discover new metabolic pathways and expand the therapeutic potential of 5hmdC and 5fdC.We profiled half maximal inhibitory concentrations (IC50) of 5hmdC and 5fdC in 45 human cancer cell lines (Table S1). The survey showed that 10 cell lines were sensitive to 5hmdC, and 19 sensitive to 5fdC (IC50< 50 μmol/L). By analyzing the mRNA level of CDA in these cell lines, we found that CDA is expressed in only two 5hmdC-sensitive and 14 5fdC-sensitive cell lines. Interestingly, a subset of cell lines lacking CDA expression, including SEM (a human acute lymphoblastic leukemia cell line) and Raji (a human B lymphoblastoid cell line), was strongly inhibited by either or both oxidized methylcytidines (Fig. 1A and Table S1), suggesting the presence of CDA-independent metabolic pathway (s) directing the cytotoxicity of 5hmdC and 5fdC. We analyzed the proliferation of SEM, Raji and MDA-MB-231 by supplementing 10 μmol/L 5hmdC or 5fdC in the culture media over a period of 7 days and found that the proliferation of SEM and Raji cell lines was significantly inhibited by 5hmdC or 5fdC (Fig. 1B), and that these two cell lines were much more sensitive to 5hmdC, 5fdC, or both, than MDA-MB-231, which expresses CDA (Fig. 1A). 5hmdC-and 5fdC-treated SEM and Raji cells showed an increased γH2AX signal (Fig. 1C), indicating that 5hmdC and 5fdC are able to induce DNA damage in the absence of CDA-directed deamination. Twenty-four hours of 5hmdC treatment resulted in S-phase arrest (Fig. S1A and S1B) and an increase in apoptosis (Fig. S1C and S1D) of SEM cells. Taken together, these data indicated that we have identified a group of cancer cells that are able to metabolize oxidized methylcytidines through CDA-independent pathway (s). Due to the inability of cytidine monophosphate kinase 1 (CMPK1) to phosphorylate modified cytidine monophosphates, the direct incorporation of 5mdC, 5hmdC and 5fdC into …
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影响因子：
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作者：
Ebrahem Q;Mahfouz RZ;Ng KP;Saunthararajah Y
通讯作者：
Saunthararajah Y
DOI：
10.1016/0027-5107(93)90186-j
发表时间：
1993-04-01
期刊：
MUTATION RESEARCH
影响因子：
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作者：
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通讯作者：
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DOI：
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发表时间：
2011-08-05
期刊：
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作者：
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通讯作者：
Nimer SD
影响因子：
14.8
作者：
Jiang, Hai;Pritchard, Justin R.;Williams, Richard T.;Lauffenburger, Douglas A.;Hemann, Michael T.
通讯作者：
Hemann, Michael T.
DOI：
10.1126/science.abb4542
发表时间：
2021-04-09
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Fugger K;Bajrami I;Silva Dos Santos M;Young SJ;Kunzelmann S;Kelly G;Hewitt G;Patel H;Goldstone R;Carell T;Boulton SJ;MacRae J;Taylor IA;West SC
通讯作者：
West SC