dehydroxymethylepoxyquinomicin and Multiple-Myeloma

There have been great advances in the therapy of cancer and leukemia. However, there are still many neoplastic diseases that are difficult to treat. For example, it is often difficult to find effective therapies for aggressive cancer and leukemia. An NF-κB inhibitor named dehydroxymethylepoxyquinomicin (DHMEQ) was discovered in 2000. This compound was designed based on the structure of epoxyquinomicin isolated from a microorganism. It was shown to be a specific inhibitor that directly binds to and inactivates NF-κB components. Until now, DHMEQ has been used by many scientists in the world to suppress animal models of cancer and inflammation. Especially, it was shown to suppress difficult cancer models, such as hormone-insensitive breast cancer and prostate cancer, cholangiocarcinoma, and multiple myeloma. No toxicity has been reported so far. DHMEQ was administered via the intraperitoneal (IP) route in most of the animal experiments because of its simplicity. In the course of developmental studies, it was found that IP administration never increased the blood concentration of DHMEQ because of the instability of DHMEQ in the blood. It is suggested that inflammatory cells in the peritoneal cavity would be important for cancer progression, and that IP administration, itself, is important for the effectiveness and safety of DHMEQ. In the present review, we describe mechanism of action, its in vivo anticancer activity, and future clinical use of DHMEQ IP therapy.

Topics: Animals; Antineoplastic Agents; Benzamides; Breast Neoplasms; Cyclohexanones; Female; Humans; Injections, Intraperitoneal; Lymphoma; Male; Mice; Multiple Myeloma; Neoplasms; NF-kappa B

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Benzamides; Calcium-Binding Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Line, Tumor; Cyclin D; Cyclin D1; Cyclins; Cyclohexanones; Disease Models, Animal; Down-Regulation; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Nerve Tissue Proteins; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Synaptotagmin I; Synaptotagmins; Translocation, Genetic; Vascular Endothelial Growth Factor A

Nuclear factor-kappaB (NF-kappaB) is constitutively activated in multiple myeloma cells. Several proteasome inhibitors have been shown to be effective against multiple myeloma and may act by inhibiting degradation of IkappaBalpha. Here, we examined the biological effects of a new type of NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is reported to directly inhibit the cytoplasm-to-nucleus translocation of NF-kappaB. A multiple myeloma cell line, 12PE, which is defective for IkappaBalpha protein, was utilized to determine if IkappaBalpha is concerned with the action of DHMEQ. Meanwhile, U266 was used as a multiple myeloma cell line with normal IkappaBalpha. A proteasome inhibitor, gliotoxin, which is an inhibitor of degradation of phosphorylated IkappaBalpha, failed to inhibit translocation of NF-kappaB in 12PE. In contrast, DHMEQ equally inhibited translocation of NF-kappaB to the nucleus and induced apoptosis to both multiple myeloma cell lines, suggesting that apoptosis resulting from DHMEQ is IkappaBalpha independent. DHMEQ also induced apoptosis in freshly isolated multiple myeloma cells. After DHMEQ treatment, cleavage of caspase-3 and down-regulation of cyclin D1 were observed in both cell lines. In addition, administration of DHMEQ resulted in a significant reduction in tumor volume in a plasmacytoma mice model compared with control mice. Our results show that DHMEQ could potentially be a new type of molecular target agent for multiple myeloma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Caspase 3; Caspases; Cyclin D1; Cyclohexanones; Down-Regulation; Drug Screening Assays, Antitumor; Enzyme Activation; Female; Humans; I-kappa B Proteins; Mice; Mice, Inbred ICR; Mice, SCID; Minor Histocompatibility Antigens; Multiple Myeloma; NF-kappa B; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured