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首页> 外文期刊>European Journal of Pharmacology: An International Journal >PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR-counterpart K562/A02 through producing reactive oxygen species
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PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR-counterpart K562/A02 through producing reactive oxygen species

机译：PHII-7通过产生活性氧来抑制白血病细胞株K562及其MDR对应物K562 / A02的细胞生长并诱导其凋亡

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摘要

Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which was designed and synthesized by our laboratory. Our preliminary work indicated its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effects in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells with the detailed mechanism remained to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was also induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results may provide a detailed biochemical basis for further clinical application of PHII-7.
机译：多药耐药性（MDR）是阻碍化学疗法在许多人类恶性肿瘤中发挥作用的主要障碍。 PHII-7是靛玉红的衍生物，由我们的实验室设计合成。我们的初步工作表明了其在体外和体内的有效抗肿瘤活性。此外，基于MDR细胞系的模型，我们发现其在抑制P-糖蛋白（P-gp）表达和杀死多药耐药（MDR）细胞方面的强大作用还有待探索的详细机制。众所周知，活性氧具有很高的反应活性，因为它们具有不匹配的电子。在这项研究中，我们表明PHII-7在亲代K562及其对应的MDR K562 / A02细胞中产生了相等的活性氧。与巯基抗氧化剂谷胱甘肽或N-乙酰半胱氨酸（NAC）预孵育几乎消除了PHII-7的细胞毒性。此外，NAC消除了PHII-7诱导的DNA损伤，细胞周期停滞和凋亡。我们的研究结果共同表明，由PHII-7诱导的活性氧物质的产生有助于MDR K562 / A02细胞的凋亡和细胞周期失速，从而扩展了我们先前的相关发现。值得注意的是，PHII-7也会诱导JNK磷酸化，并与NAC或JNK抑制剂（SP006125）预孵育K562 / A02细胞，从而消除P-gp下调。综上所述，我们的结果可能为PHII-7的进一步临床应用提供详细的生化基础。

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