Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation.
Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation.
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TMZ-POH对人鼻咽癌的治疗作用取决于活性氧的积累。
DOI：
10.18632/oncotarget.6410
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Song X
中科院分区：
文献类型：
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作者：
Xie L;Song X;Guo W;Wang X;Wei L;Li Y;Lv L;Wang W;Chen TC;Song X
鼻咽癌（Nasopharyngeal carcinoma，NPC）是一种常见的头颈部恶性肿瘤，目前尚无有效的化疗药物，本研究观察了新型专利化合物替莫唑胺-紫苏醇（Temozolomide-perillyl alcohol，TMZ-POH）对NPC的细胞毒作用，并探讨了其可能的作用机制。用对照（DMSO）、TMZ、POH、TMZ + POH和TMZ-POH处理人NPC细胞系CNE 1、CNE 2、HNE 2和SUME-α。结果表明TMZ-POH可抑制鼻咽癌细胞增殖，导致细胞G2/M期阻滞和DNA损伤。TMZ-POH通过显著激活caspase-3和聚（ADP-核糖）聚合酶（PARP）引发NPC细胞凋亡。重要的是，发现TMZ-POH诱导的细胞死亡与（i）线粒体内膜电位（Δ μ m）的丧失和线粒体细胞色素c的释放，（ii）ROS生成的增加，以及（iii）应激激活蛋白激酶（SAPK）/c-Jun N-末端激酶（JNK）信号通路的激活相关。由于使用抗氧化剂N-乙酰-L-半胱氨酸或过氧化氢酶阻断ROS产生逆转了TMZ-POH诱导的JNK激活、DNA损伤和癌细胞凋亡，因此响应于TMZ-POH的ROS的产生似乎在细胞死亡过程中起关键作用。这些结果为TMZ-POH抗鼻咽癌的进一步研究和临床前研究提供了理论依据。
Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy without efficient chemotherapeutic agents for it. In our current study, we demonstrated the cytotoxicity effects of a newly patented compound temozolomide–perillyl alcohol (TMZ-POH) on NPC in vitro and in vivo, and the possible mechanisms involved. Human NPC cell lines CNE1, CNE2, HNE2, and SUME-α were treated with control (DMSO), TMZ, POH, TMZ plus POH, and TMZ-POH. Our data indicated that TMZ-POH could inhibit NPC cell proliferation, cause G2/M arrest and DNA damage. TMZ-POH triggered apoptosis in NPC cells via significant activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). Importantly, TMZ-POH-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial Cytochrome c, (ii) the increase in ROS generation, and (iii) the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinases (JNK) signaling pathway. The generation of ROS in response to TMZ-POH seems to play a crucial role in the cell death process since the blockage of ROS production using the antioxidant N-acetyl-L-cysteine or catalase reversed the TMZ-POH-induced JNK activation, DNA damage, and cancer cell apoptosis. These results provide the rationale for further research and preclinical investigation of the antitumor effect of TMZ-POH against human NPC.