Wang Duoduo, Zhu Qionghua, Zhang Xiayan, Zhang Lei, He Qiaojun, Yang Bo
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Pharmazie. 2010 Jan;65(1):51-6.
Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature, which is recognized to play a role in the resistance of cancer cells to chemotherapy. Etoposide (VP-16), a drug commonly used in chemotherapy, leads to enhanced accumulation of cell populations in G2/M phase and increases levels of apoptosis as a topoisomerase II inhibitor. We evaluated the effects of hypoxia on the response of the neuroblastoma cell line CHP126 to VP-16, in order to delineate the mechanisms responsible for the hypoxia-induced chemoresistance of this clinically conventional anti-cancer agent, with an insight to determining potential indications in neuroblastoma therapy. In this study, physiological hypoxia was shown to attenuate G2/M arrest and apoptosis induced in CHP126 cells by VP-16. It suppressed drug-related Cdk1 activity with a less elevation of regulator proteins such as cyclin B1, Cdk7 and reduced caspase activation and PARP cleavage compared to the efficiency observed in normoxic condition, which were significantly relative with hypoxia-driven inhibition of p53 and p-ERK1/2 activation. These results clearly demonstrated that hypoxia had a protective effect against VP-16-induced cytotoxicity, which is likely to provide a further therapeutic knowledge in neuroblastomas.
由于肿瘤衍生的新生血管结构不良，缺氧在实体瘤中广泛存在，已知其在癌细胞对化疗的耐药性中起作用。依托泊苷（VP-16）是化疗中常用的药物，作为一种拓扑异构酶II抑制剂，可导致细胞群体在G2/M期的积累增加，并增加细胞凋亡水平。我们评估了缺氧对神经母细胞瘤细胞系CHP126对VP-16反应的影响，以阐明这种临床常用抗癌药物缺氧诱导化疗耐药性的机制，以期确定神经母细胞瘤治疗中的潜在适应症。在本研究中，生理缺氧被证明可减弱VP-16诱导的CHP126细胞的G2/M期阻滞和细胞凋亡。与常氧条件下观察到的效率相比，它抑制了与药物相关的Cdk1活性，同时调节蛋白如细胞周期蛋白B1、Cdk7的升高较少，并且降低了半胱天冬酶激活和PARP裂解，这与缺氧驱动的p53抑制和p-ERK1/2激活显著相关。这些结果清楚地表明，缺氧对VP-16诱导的细胞毒性具有保护作用，这可能为神经母细胞瘤提供进一步的治疗知识。
