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Our findings suggest that Tan-IIA causes G0/G1 cell cycle arrest in LNCaP cells and its cytotoxicity is mediated at least partly by ER stress induction. These data provide evidence supporting Tan-IIA as a potential anticancer agent by inducing ER stress in prostate cancer.

Arsenic compounds, which are well-documented human carcinogens, are now used in cancer therapy. Knowledge of the mechanism by which arsenic exerts its toxicity may help in designing a more effective regimen for therapy. In this study, we showed that arsenite could induce prominent mitotic arrest in CGL-2 cells and demonstrated the presence of damaged DNA in arsenite-arrested mitotic cells. We then explored why these cells with arsenite-induced DNA damage were arrested at mitosis instead of G2 stage. When synchronized CGL-2 cells were treated with arsenite at stage G1, S or G2, all progressed into, and arrested at, the mitotic stage and contained damaged DNA, as demonstrated by the appearance of the DNA double-strand break marker, phosphorylated histone H2A.X (gamma-H2AX). Since X-irradiation induced G2 arrest in CGL-2 cells, these cells clearly have a functional G2 DNA damage checkpoint. However, treatment of X-irradiated CGL-2 cells with arsenite resulted in a decrease in G2 cells and an increase in mitotic cells, suggesting that arsenite may inhibit activation of the G2 DNA damage checkpoint and thus allow cells with damaged DNA to proceed from G2 into mitosis. Immunoblot analysis confirmed that arsenite treatment reduced the X-irradiation-induced phosphorylation of both ataxia-telangiectasia, mutated at serine 1981 and Cdc25C at serine 216, events which are crucial for G2 checkpoint activation and G2 arrest. Moreover, a higher frequency of apoptotic cells is observed in mitotic CGL-2 cells arrested by arsenite than those arrested by nocodazole or taxol. Our results show that the combined effects of arsenite in inducing DNA damages, inhibiting the activation of G2 checkpoint, and arresting cells with damaged DNA in the mitotic stage may subsequently enhance the induction of apoptosis in arsenite-arrested mitotic CGL-2 cells.

The expression of GABAA/benzodiazepine beta subunit mRNAs was studied in cerebral cortex, hippocampus, and cerebellum of flurazepam-treated rats. Immediately following 4 wk of treatment, beta 2 and beta 3 subunit mRNAs were significantly reduced in cerebellum and hippocampus, whereas only beta 2 was decreased in cortex. These decreases had largely reversed 48 h following flurazepam treatment. After 2 wk of treatment, both beta 2 and beta 3 mRNAs were reduced in cerebellum, and beta 3 mRNA was reduced in hippocampus, but neither was changed in cortex. Four hours after an acute flurazepam treatment, the only change was a decrease in beta 3 mRNA in hippocampus. These results indicate that the expression of GABAA receptor beta subunit mRNAs in different brain regions is differentially regulated during chronic flurazepam treatment, and some changes occur within hours after a single large dose.