chaetocin and Multiple-Myeloma

Dendritic cells (DC)-based vaccines are considered useful in cancer immuno-therapy, and the interactions of DC and dying tumor cells are important and promising for cancer immunotherapy. We investigated whether chaetocin could be used to induce death of myeloma cells, for loading onto DCs can affect DCs function. In this study, we show that the dying myeloma cells treated with chaetocin resulted in the induction of heat shock protein (HSP) 90, which was inhibited by antioxidant N-acetyl cysteine, and showed an increase in the expression of MAGE-A3 and MAGE-C1/CT7. DCs loaded with chaetocin-treated dying myeloma cells produced low levels of IL-10 and enhanced the cross presentation of DCs. Additionally, these DCs most potently inhibited regulatory T cells, induced Th1 polarization and activated myeloma-specific cytotoxic T lymphocytes compared with DCs loaded with UVB-irradiated dying myeloma cells. These results suggest that the pretreatment of myeloma cells with chaetocin can enhance DC function through the up-regulation of HSP90 and cancer testis antigens in dying myeloma cells and can potently induce the Th1 polarization of DCs and myeloma-specific cytotoxic T lymphocytes.

Topics: Antigens, Neoplasm; Apoptosis; B-Lymphocytes; Cancer Vaccines; Cell Line, Tumor; Cross-Priming; Dendritic Cells; HSP90 Heat-Shock Proteins; Humans; Immunotherapy, Adoptive; Interleukin-10; Lymphocyte Activation; Multiple Myeloma; Neoplasm Proteins; Piperazines; T-Lymphocytes, Cytotoxic; Ultraviolet Rays; Up-Regulation

Chaetocin, a thiodioxopiperazine natural product previously unreported to have anticancer effects, was found to have potent antimyeloma activity in IL-6-dependent and -independent myeloma cell lines in freshly collected sorted and unsorted patient CD138(+) myeloma cells and in vivo. Chaetocin largely spares matched normal CD138(-) patient bone marrow leukocytes, normal B cells, and neoplastic B-CLL (chronic lymphocytic leukemia) cells, indicating a high degree of selectivity even in closely lineage-related B cells. Furthermore, chaetocin displays superior ex vivo antimyeloma activity and selectivity than doxorubicin and dexamethasone, and dexamethasone- or doxorubicin-resistant myeloma cell lines are largely non-cross-resistant to chaetocin. Mechanistically, chaetocin is dramatically accumulated in cancer cells via a process inhibited by glutathione and requiring intact/unreduced disulfides for uptake. Once inside the cell, its anticancer activity appears mediated primarily through the imposition of oxidative stress and consequent apoptosis induction. Moreover, the selective antimyeloma effects of chaetocin appear not to reflect differential intracellular accumulation of chaetocin but, instead, heightened sensitivity of myeloma cells to the cytotoxic effects of imposed oxidative stress. Considered collectively, chaetocin appears to represent a promising agent for further study as a potential antimyeloma therapeutic.

Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Cell Lineage; Cell Survival; Coculture Techniques; Dexamethasone; Doxorubicin; Glutathione; Histones; Humans; Interleukin-6; Leukemia, Lymphocytic, Chronic, B-Cell; Membrane Potential, Mitochondrial; Mice; Mice, SCID; Microscopy, Electron, Transmission; Multiple Myeloma; Oxidative Stress; Piperazines; Syndecan-1; Tumor Cells, Cultured; Xenograft Model Antitumor Assays