The cobalt(II) complex salts [Co(bpy)(az)2](PF6)2 and [Co(az)4](PF6), each bearing the unusual cis-N,N′-diphenylazodioxide ligand, were both screened as possible anticancer agents against SK-HEP-1 liver cancer cells. Both compounds were found to induce substantial apoptosis as an increasing function of concentration and time. Measurement of apoptosis-related proteins indicated that both the extrinsic and intrinsic pathways of apoptosis were activated. The apoptotic activity induced by these salts is not displayed either by simple cobalt(II) salts or complexes or by the free nitrosobenzene ligand. Additionally, these compounds did not induce apoptosis, as assessed by poly(adenosine diphosphate-ribose) polymerase cleavage, in several other cell lines.

Prostate cancer is the second most commonly diagnosed cancer among men in the United States. Prostate cancer therapy is severely hampered by lack of response and development of resistance to conventional chemotherapeutic drugs in patients. Therefore, the development and discovery of new drugs have become an urgent clinical need. Interferons (IFNs), a family of pleiotropic cytokines, exert antitumor activities due to their anti-proliferative, immunomodulatory and proapoptotic functions. Here, we report that pretreatment of prostate cancer PC-3 cells with IFNs sensitized these cells to double-stranded RNAs (dsRNAs)-induced apoptosis. The enhancement effect of IFN treatment was dependent on IFN subtypes, in particular, IFN γ. In comparison with IFN α or β, IFN γ treatment remarkably augmented apoptosis in PC-3 cells induced with polyinosinic:polycytidylic acid (poly I:C), a synthesized form of dsRNA. We demonstrated that IFN-signaling was necessary for these effects by using mutant cell lines. Transfection of 2–5A, the activator of RNase L, or silencing of dsRNA-dependent protein kinase R (PKR) by siRNA did not have any significant impact on this event, suggesting that neither RNase L nor PKR was involved in poly I:C/IFN γ-induced apoptosis in the cells. Further investigation of the apoptotic pathway revealed that Bak, a pro-apoptotic member of the Bcl-2family, was synergistically up-regulated by IFN γ and poly I:C, whereas other members of the family were not affected. Knocking down of Bak demonstrated its contribution to poly I:C/IFN γ-induced apoptosis in the cells. We believeour findings will precipitate the design of novel therapeutic strategies for prostate cancer.

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CorrectionFigure 1: Effect of poly I:C and IFNs on PC-3 cell viability. PC-3 cells were treated with 1,000 unit/ml IFN α, β or γ overnight and transfected with and without 1 μg/ml poly I:C in the presence of lipofectamine. A. The viable cells were analyzed by trypan blue exclusion assays and the cell numbers were averaged from three independent experiments. Error bars represent ±SEM, and Student's t test was used.

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