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.
Flavonoids isolated from Citrus platymamma induced G2/M cell cycle arrest and apoptosis in A549 human lung cancer cells