6-Shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism
6-Shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism
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DOI：
10.1021/jf0624594
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发表时间：
2007-02-07
影响因子：
6.1
通讯作者：
Chen, Ching-Hsein
中科院分区：
文献类型：
--
作者：
Chen, Chung-Yi;Liu, Tsan-Zon;Chen, Ching-Hsein
Mahlavu细胞是人类肝癌亚系的低分化p53突变体，由于其多药耐药基因-1 （MDR-1）和Bcl-2蛋白的高表达，已知对许多化疗药物和放疗具有高度难治性。因此，寻找一种有效根除这种类型癌细胞的替代策略是可取的。本研究首次证实，从生姜根茎中分离的烷酮6-shogaol （6-SG）可以通过氧化应激介导的caspase依赖机制有效诱导Mahlavu细胞凋亡。6- sg诱导这些细胞凋亡的级联事件包括最初活性氧（ROS）的过量产生，随后是细胞内谷胱甘肽（GSH）含量的严重消耗。这两个事件导致线粒体跨膜电位（δ Psi(m)）显著下降，最终激活半胱天冬酶3/7的活性，导致DNA断裂。有趣的是，我们还发现n -乙酰半胱氨酸（NAC），一种抗氧化剂和谷胱甘肽生物合成的前体，可以对6-SG造成的凋亡细胞死亡提供近乎完全的保护。同样，外源添加谷胱甘肽也能提供相同效果的保护。然而，Boc-Asp(OMe)-fmk（一种广泛的半胱天冬酶抑制剂）和环孢素a（一种线粒体通透性过渡开放抑制剂）只能部分保护这些细胞免受6- sgg诱导的凋亡，这是矛盾的。考虑到这些数据，很明显GSH耗竭是6- sg诱导的Mahlavu细胞凋亡的主要因素。总之，我们在这里提供了一种新的模式，可以帮助根除人类肝癌细胞的p53突变，通过使用天然一致的分离形式的生姜。这些数据还提供了证据，重申了这样一种观点，即食用某些食品可能对健康有益，因为它们所含的某些成分可能具有抗癌作用。
Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (Delta Psi(m)), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.