TPEN 通过氧化应激和线粒体 caspase-3 和 AIF 依赖性途径在急性淋巴细胞白血病和离体急性白血病细胞模型中独立于锌螯合剂活性诱导细胞凋亡。,Oxidative Medicine and Cellular Longevity

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TPEN 通过氧化应激和线粒体 caspase-3 和 AIF 依赖性途径在急性淋巴细胞白血病和离体急性白血病细胞模型中独立于锌螯合剂活性诱导细胞凋亡。
Oxidative Medicine and Cellular Longevity Pub Date : 2012-12-23 , DOI: 10.1155/2012/313275
Miguel Mendivil-Perez ₁ , Carlos Velez-Pardo , Marlene Jimenez-Del-Rio

Affiliation

急性淋巴细胞白血病仍然是一种无法治愈的疾病，大多数患者对治疗产生耐药性。我们研究了 TPEN（一种细胞内锌螯合剂）在 Jurkat 和体外对化疗耐药的急性淋巴细胞白血病 (ALL) 细胞中的作用。细胞核形态的变化、活性氧的产生、亚二倍体细胞的存在、磷脂酰丝氨酸易位、线粒体膜去极化、细胞死亡信号分子的免疫组织化学鉴定和药理学抑制被测定以检测凋亡细胞死亡途径。我们发现 TPEN 通过涉及-κ B (JNK/c-Jun)丢失的分子氧化应激途径诱导两种类型细胞的凋亡caspase-3、AIF > 染色质凝聚/DNA 片段化。有趣的是，TPEN 独立于葡萄糖诱导细胞凋亡；因此，白血病细胞因对治疗的代谢抵抗而缺乏生存能力。最重要的是，TPEN 的细胞毒性作用最终可以通过抗氧化剂 N-乙酰半胱氨酸和锌离子进行调节。我们的数据表明 TPEN 可用作治疗难治性白血病的潜在治疗性促氧化剂。这些数据有助于理解氧化应激在 ALL 治疗中的重要性。

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TPEN induces apoptosis independently of zinc chelator activity in a model of acute lymphoblastic leukemia and ex vivo acute leukemia cells through oxidative stress and mitochondria caspase-3- and AIF-dependent pathways.

Acute lymphoblastic leukemia is still an incurable disease with resistance to therapy developing in the majority of patients. We investigated the effect of TPEN, an intracellular zinc chelator, in Jurkat and in ex vivo acute lymphoblastic leukemia (ALL) cells resistant to chemotherapy. Changes of nuclei morphology, reactive oxygen species generation, presence of hypodiploid cells, phosphatidylserine translocation, mitochondrial membrane depolarization, immunohistochemical identification of cell death signalling molecules, and pharmacological inhibition were assayed to detect the apoptotic cell death pathways. We found that TPEN induces apoptosis in both types of cells by a molecular oxidative stress pathway involving -κB (JNK/c-Jun) loss caspase-3, AIF > chromatin condensation/DNA fragmentation. Interestingly, TPEN induced apoptosis independently of glucose; leukemic cells are therefore devoid of survival capacity by metabolic resistance to treatment. Most importantly, TPEN cytotoxic effect can eventually be regulated by the antioxidant N-acetyl-cysteine and zinc ions. Our data suggest that TPEN can be used as a potential therapeutic prooxidant agent against refractory leukemia. These data contribute to understanding the importance of oxidative stress in the treatment of ALL.

更新日期：2012-12-23

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