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Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner ( P < 0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide-induced apoptosis and the downregulation of COX-2 and survivin ( P < 0.05). In vivo , nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo . [ABSTRACT FROM AUTHOR]

Abstract: Aim: It is of clinical importance to find methods to overcome bortezomib resistance. In the current study, we clarified the relationship between resistance to bortezomib and the differentiation status of myeloma cells, and explored the feasibility of induction of differentiation in overcoming bortezomib resistance in myeloma. Methods: Cell morphology, immunoglobulin light-chain protein secretion levels, and XBP-1 expression were used to evaluate the differentiation status of myeloma cells. Low dose 2-ME2 alone or in combination with ATRA was used to induce differentiation in myeloma cells. Results: The differentiation status of myeloma cells was related to myeloma sensitivity to bortezomib. After successful induction of differentiation, the myeloma cells were more sensitive to bortezomib with decreased growth and an increased rate of apoptosis. Induction of differentiation increased the proteasome workload in myeloma cells by increasing immunoglobulin secretion, while reducing proteasome capacity by decreasing proteasome activity. The imbalance between increased proteasome workload and decreased proteasome capacity is a possible mechanism by which induction of differentiation overcomes myeloma resistance to bortezomib. Conclusion: The current study demonstrated, for the first time, that myeloma differentiation status is associated with myeloma sensitivity to bortezomib and that induction of differentiation can overcome myeloma resistance to bortezomib. [Copyright &y& Elsevier]