cucurbitacin-i and Multiple-Myeloma

Signal transducer and activator of transcription 3 (STAT3) is highly activated in multiple myeloma. Activated STAT3 promotes survival and proliferation of cancer cells, suppresses Th1 immune response, and induces dysfunction of immune cells. We investigated whether pretreating myeloma cells with a phosphor (p)-STAT3 inhibitor (JSI-124) and/or bortezomib before loading into dendritic cells (DCs) can affect DC function. The combination treatment with JSI-124 and bortezomib resulted in the highest expression of heat shock protein (HSP) 90 and the lowest expression of p-STAT3 in dying myeloma cells. DCs loaded with dying myeloma cells treated by JSI-124 and bortezomib produced the least amount of p-STAT3 compared to other treatments. The DCs were recovered from abnormal cytokine secretions of interleukin (IL)-10, IL-6, and IL-23 without any effect on production of IL-12p70. DCs loaded with JSI-124 and bortezomib treated, dying myeloma cells most potently generated myeloma-specific cytotoxic T lymphocytes (CTLs). The data suggest that pretreatment of myeloma cells with JSI-124 and bortezomib can recover DC function through the up-regulation of HSP90 and the down-regulation of p-STAT3 and inhibitory cytokines, and that these DCs can potently generate myeloma-specific CTLs.

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; CD8-Positive T-Lymphocytes; Cell Death; Cytokines; Dendritic Cells; Down-Regulation; Female; Humans; Male; Multiple Myeloma; Pyrazines; STAT3 Transcription Factor; Triterpenes; Tumor Cells, Cultured; Up-Regulation