Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells
Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells
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DOI：
10.4161/cbt.6.11.4860
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发表时间：
2007-11-01
影响因子：
3.6
通讯作者：
Ding, Jian
中科院分区：
文献类型：
--
作者：
Cai, Yujun;Lu, Jinjian;Ding, Jian
沙威辛是一种新型的二萜醌类化合物，在体内外均表现出较强的抗肿瘤活性，目前正在进行肿瘤治疗的II期临床试验。我们前期的研究表明，salvicine能有效杀伤多药耐药（MDR）细胞，并通过激活MDR K562/A02细胞中的转录因子c-Jun下调MDR-1和P-gp的表达。近年来的研究进一步表明，丹参素形成的活性氧簇（ROS）有助于其诱导细胞毒性、DNA双链断裂和细胞凋亡。在这项研究中，我们发现，salvicine诱导相同的活性氧产生和谷胱甘肽消耗敏感的K562和MDR K562/A02细胞。巯基抗氧化剂谷胱甘肽或N-乙酰半胱氨酸（NAC，细胞内谷胱甘肽的前体）的预孵育几乎取消了salvicine的细胞毒性，这也可以由H2 O2特异性清除剂过氧化氢酶减弱。此外，NAC取消salvicine诱导的DNA双链断裂和细胞凋亡。值得注意的是，H2 O2和维生素C都增强了salvicine对亲本K562和MDR K562/A02细胞的细胞毒性和凋亡诱导作用，而catolase可以消除这种增强作用。NAC预处理K562/A02细胞后，salvicine诱导的P-gp表达下调、JNK磷酸化及c-Jun活化均被NAC抑制。我们的数据共同表明，salvicine产生的ROS有助于MDR K562/A02细胞的细胞杀伤和P-gp下调，从而扩展了我们以前的相关研究。本研究也为将来沙文辛与维生素C联合治疗开辟了可能性。
Salvicine, a novel diterpenoid quinone compound, displays potent antitumor activities in vitro and in vivo, which is under Phase II clinical trials for cancer therapy. Our previous studies have shown that salvicine effectively kills multidrug-resistant (MDR) cells and downregulates mdr-1 and P-glycoprotein (P-gp) levels by activation of transcription factor c-Jun in MDR K562/A02 cells. Recent studies have further demonstrated that salvicine-formed reactive oxygen species (ROS) contribute to its induction of cytotoxicity, DNA double strand breaks and apoptosis. In this study, we showed that salvicine induced equal ROS generation and glutathione depletion in both sensitive K562 and MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine (NAC, precursor of intracellular glutathione) almost abolished the cytotoxicity of salvicine, which also could be attenuated by the H2O2-specific scavenger catalase. Moreover, NAC abrogated salvicine-induced DNA double strand breaks and apoptosis. Notably, both H2O2 and vitamin C potentiated the cytotoxicity and apoptotic induction of salvicine in parental K562 and MDR K562/A02 cells, and catolase could remove such potentiation. Furthermore, pretreatment of K562/A02 cells with NAC eliminated P-gp, downregulation, JNK phosphorylation and c-Jun activation induced by salvicine. Our data collectively indicate that salvicine-generated ROS contribute to both cell killing and P-gp downregulation in MDR K562/A02 cells, thus extending our prior related studies. This study also opens the possibility of the combination therapy of salvicine and vitamin C in the future.