Diethyldithiocarbamate-induced cytotoxicity and apoptosis in leukemia cell lines.
Diethyldithiocarbamate-induced cytotoxicity and apoptosis in leukemia cell lines.
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DOI：
10.1248/bpb.26.964
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发表时间：
2003-07
影响因子：
2
通讯作者：
Syu-ichi Kanno;Emi Matsukawa;A. Miura;Ai Shouji;Keiko Asou;M. Ishikawa
中科院分区：
文献类型：
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作者：
Syu-ichi Kanno;Emi Matsukawa;A. Miura;Ai Shouji;Keiko Asou;M. Ishikawa
二乙基二硫代氨基甲酸酯（DDTC）已被证明在几个不同的系统中诱导细胞毒性。我们研究了DDTC诱导的细胞毒性是否是通过细胞凋亡，或与细胞内谷胱甘肽（GSH）在各种小鼠和人类白血病细胞系。对DDTC诱导的细胞毒作用最敏感的细胞是P388淋巴瘤细胞和急性淋巴细胞白血病（ALL）的B细胞系NALM-6。下一级别的易感细胞包括具有巨噬细胞功能的J774.1、HL-60前髓细胞白血病细胞、急性淋巴细胞白血病细胞MOLT-4和T细胞白血病细胞Jurkat。U937（表达许多单核细胞样特征）、K562红白血病和K562/DXR（K562衍生的多药耐药克隆）几乎不受DDTC的影响。P388对H2 O2（一种最有用的外源性活性氧产生剂）也高度敏感，且细胞内总GSH含量低于其它白血病细胞。DDTC诱导的细胞毒性与细胞内GSH水平密切相关，但细胞内GSH水平与H2 O2诱导的细胞毒性并不总是相关的。K562细胞内总GSH含量较高，对DDTC和H2 O2的敏感性较低，但DDTC与DL-丁硫基-（S，R）-亚砜亚胺（BSO）联合使用时，细胞毒作用明显增强。DDTC和H2 O2均使P388细胞GSH/GSSG比值降低。过氧化氢酶（CAT）可完全阻断H2 O2诱导的细胞毒作用，而超氧化物歧化酶（SOD）可增强H2 O2诱导的细胞毒作用。CAT和SOD对DDTC诱导的细胞毒性无影响。N-乙酰半胱氨酸（NAC：1 mM），GSH的先锋物质，和金精三羧酸（ATA：100 microM），一种核酸内切酶抑制剂，改善DDTC诱导的细胞毒性和细胞凋亡。总之，我们认为DDTC诱导的细胞毒性是通过细胞内氧化还原状态的氧化转变，并伴随着核酸内切酶的激活，通过凋亡在白血病细胞系。
Diethyldithiocarbamate (DDTC) has been shown to induce cytotoxicity in several different systems. We examined whether the DDTC-induced cytotoxicity was via apoptosis, or in relation to intracellular glutathione (GSH) in various murine and human leukemia cell lines. The cells most sensitive to DDTC-induced cytotoxicity were P388 lymphoid neoplasma cells and NALM-6, a B cell line of acute lymphocytic leukemia (ALL). The next level of susceptible cells included J774.1, having a macrophage function, HL-60 premyelocytic leukemia cells, MOLT-4, an acute lymphoblastic leukemia cell, and Jurkat, a T-cell leukemia. U937 (expressing many monocyte-like characteristics), K562 erythroleukemia and K562/DXR (a multidrug-resistant clone derived from K562) were almost unaffected by DDTC. P388 was also highly susceptible to H(2)O(2), a most useful exogenous reactive oxygen species generator, and was lower in intracellular total GSH content than other leukemia cells. DDTC-induced cytotoxicity was closely related to intracellular GSH, but the level of cellular GSH did not always correlate with H(2)O(2)-induced cytotoxicity in this experiment. K562 had a higher intracellular total GSH content and showed lower susceptibility to DDTC and H(2)O(2), but with the combination of DDTC and DL-buthionine-(S,R)-sulfoximine (BSO), cytotoxicity increased significantly. The ratio of GSH/GSSG in P388 was reduced by DDTC or H(2)O(2). H(2)O(2)-induced cytotoxicity was completely blocked by catalase (CAT), while it was enhanced by superoxide dismutase (SOD). CAT or SOD did not affect DDTC-induced cytotoxicity. N-Acetylcysteine (NAC: 1 mM), a vanguard substance of GSH, and aurintricarboxylic acid (ATA: 100 microM), an endonuclease inhibitor, ameliorated DDTC-induced cytotoxicity and apoptosis. In conclusion, we suggest that DDTC-induced cytotoxicity was via an oxidative shift in the intracellular redox state, and accompanied the activation of endonuclease through apoptosis in leukemia cell lines.