Involvement of NO generation in aluminum-induced cell death.

Previously, we have reported that the exposure of PC12 cells to the aluminum-maltolate complex (Al(maltol)(3)) results in decreased cell viability via the apoptotic cell death pathway. In this study, we have used several nitric oxide synthase (NOS) inhibitors and the NO generator diethylenetriamine NONOate (DETA NONOate) to examine whether or not intracellular nitric oxide (NO) generation is involved in the onset mechanism of Al(maltol)(3)-induced cell death. Cell viability was assessed by measuring lactate dehydrogenase (LDH) release and caspase-3 activity. Treatment of the cells with 150 microM Al(maltol)(3) for 48 h resulted in intracellular NO generation. Exposure of the cells to DETA NONOate also induced a marked decrease in cell viability. Pre-treatment of the cells with a general NOS inhibitor or with a selective inducible NOS (iNOS) inhibitor effectively prevented Al(maltol)(3)-induced cell death. However, a neuronal NOS (nNOS) inhibitor did not exhibit any protective effect against Al(maltol)(3)-induced cell death. In addition, ascorbic acid markedly inhibited Al(maltol)(3)- and DETA NONOate-induced cell death. Based on these results, we discussed the involvement of intracellular NO generation in the onset mechanisms of Al(maltol)(3)-induced cell death.

Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor.

Emodin is an active component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L. Here, we show that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6-induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1-overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. In conclusion, emodin inhibits interleukin-6-induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, our results show emodin as a new potent anticancer agent for the treatment of multiple myeloma patients.