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Arsenic trioxide inhibits the growth of human lung cancer cell lines via cell cycle arrest and induction of apoptosis at both normoxia and hypoxia

Department of Respiratory Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China

Xiu Qing-Yu

Department of Respiratory Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China, doctorxiuqy{at}163.com

Li Bing

Department of Respiratory Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China

Liu Yong-an

Department of Respiratory Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China

Zhang Ling-Zhen

Department of Laboratory Diagnosis, Changzheng Hospital, Second Military Medical University, Shanghai, China

Arsenic trioxide (As ₂O₃) has been established to be an effective agent for treating acute promyleocytic leukemia. Laboratory data suggest that As₂O ₃ induces apoptosis of several solid tumor cells including lung cancer cells. Regions of tissue hypoxia often arise in aggressive solid tumors, and hypoxic tumors exhibit augmented invasiveness and metastatic ability in several malignancies. Furthermore, hypoxia may impair the treatment efficiency; therefore, we studied the cytotoxic effect of As₂O₃ on human lung adenocarcinoma cell lines A549 and A549/R (resistant to vincristine, adriamycin and mitomycin etc.) grown under normoxic and hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 5, 10 and 15 µM As₂O₃ induced evident growth inhibition and apoptosis in A549 cells as well as A549/R cells after 48 hours of exposure. In contrast, the conventional chemotherapeutic drug vincristine showed lowered efficiency in hypoxic A549 cells. As₂O₃ induced G₂/M cell cycle arrest in both normoxic and hypoxic A549 cells. As₂O₃ significantly decreased the messenger RNA (mRNA) levels of Cyclin B₁ and survivin and the protein levels of Cyclin B₁, phospho-CDC₂ (Thr 161) and survivin in both normoxic and hypoxic A549 cells. Together, our findings indicated that As₂O₃ significantly inhibited the proliferation of lung cancer cells via G₂/M cell cycle arrest and induction of apoptosis at both normoxia and hypoxia, and the induction of apoptosis was associated with down regulation of survivin.

Key Words: Hypoxia • arsenic trioxide • lung cancer • apoptosis • cell cycle • Cyclin B1/CDC2 complex • surviving

Toxicology and Industrial Health, Vol. 25, No. 8, 505-515 (2009)
DOI: 10.1177/0748233709345936


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