Hypoxia promotes etoposide (VP-16) resistance in neuroblastoma CHP126 cells.
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.
Wang
Duoduo
D
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Zhu
Qionghua
Q
Zhang
Xiayan
X
Zhang
Lei
L
He
Qiaojun
Q
Yang
Bo
B
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005434:Flow Cytometry; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D009363:Neoplasm Proteins; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases