dehydroxymethylepoxyquinomicin and Neoplasms

Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.

Topics: Actinobacteria; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Movement; Cyclohexanones; Glyoxylates; Humans; Matrix Metalloproteinase 11; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Models, Molecular; Neoplasm Invasiveness; Neoplasms; NF-kappa B; NF-kappa B p50 Subunit; Quinones

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

We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.

Topics: Animals; Antineoplastic Agents; Benzamides; Cyclohexanones; Humans; Neoplasm Metastasis; Neoplasms; NF-kappa B; Quinones

NF-κB is a transcription factor and considered to be involved in the mechanisms of inflammation and cancer. We have designed the new NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which directly binds to a specific cysteine residue of Rel family proteins to inhibit their DNA-binding activity. DHMEQ showed potent anti-inflammatory and anticancer activities in many animal models. So far DHMEQ has been administered mainly into the peritoneal cavity of animals. According to the limited distribution of DHMEQ in the peritoneal cavity after intraperitoneal administration, it is likely that NF-κB in the peritoneal cells would be the main target of DHMEQ. Therefore, the inflammatory cells in the peritoneal cavity appear important for the regulation of peripheral inflammation and tumor growth in the body, and peritoneal NF-κB may be an important target for anti-inflammatory and anticancer agents in future.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cyclohexanones; Humans; Inflammation; Molecular Structure; Neoplasms; NF-kappa B; Peritoneum

Tumors develop resistance to cytotoxic apoptotic stimuli induced by various chemotherapeutic drugs and immunotherapies. Therefore, there is a need to overcome chemo- and immuno-resistance of tumors through the development of small molecules, as sensitizing agents, aimed at targeting gene products that regulate the apoptotic pathways and allow therapeutics to be effective. The constitutively activated NF-kappaB (nuclear factor kappa B) signaling pathway is involved in cell survival, inflammation and metastasis and is invariably constitutively activated in most cancers. Consequently, NF-kappaB is intimately involved in the regulation of resistance to cytotoxic drugs. A novel NF-kappaB inhibitor, DHMEQ (dehydroxymethylepoxyquinomicin), inhibits the translocation of NF-kappaB into the nucleus as well as inhibits DNA binding of NF-kappaB components and was shown to be a potent chemo- and immuno-sensitizing agent and in combination with cytotoxic therapeutics resulted in significant reversal of resistance and tumor cell death. This review will present various lines of evidence supporting the therapeutic efficacy of DHMEQ when used in combination with conventional/new cytotoxic drugs in the treatment of resistant tumor cells as well as in the prevention of metastasis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Cyclohexanones; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Neoplasms; NF-kappa B

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Biological Products; Cell Differentiation; Cyclohexanones; Depsipeptides; Drug Design; Drug Evaluation, Preclinical; Inflammation; Inflammation Mediators; Lipopolysaccharides; Neoplasms; NF-kappa B; Osteoclasts; Piperidones; Signal Transduction

NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. NF-kappaB is often constitutively activated in human cancers and leukemias, which might increase the malignant character of neoplastic diseases. Therefore, NF-kappaB inhibitors might be useful as anticancer agents. Our research team designed a new NF-kappaB inhibitor that is based on the structure of the antibiotic epoxyquomicin C isolated from a microorganism. The designed compound, DHMEQ, inhibited the ligand-induced activation of NF-kappaB, and it also inhibited the constitutively activated NF-kappaB in cancer cells. DHMEQ is a unique inhibitor of NF-kappaB that acts at the level of the nuclear translocation. It inhibited both canonical and non-canonical NF-kappaB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent.

Topics: Animals; Antineoplastic Agents; Benzamides; Cell Proliferation; Cyclohexanones; Drug Design; Humans; Neoplasms; NF-kappa B; Quinones; Signal Transduction; Tumor Cells, Cultured

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the Spint1 gene, is a membrane-bound serine protease inhibitor expressed on the epithelial cell surface. We have previously reported that the intestine-specific Spint1-deleted ApcMin/+ mice showed accelerated formation of intestinal tumors. In this study, we focused on the role of nuclear factor-κB (NF-κB) signaling in the HAI-1 loss-induced tumor susceptibility. In the HAI-1-deficient intestine, inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, were upregulated in normal mucosa. Furthermore, increased nuclear translocation of NF-κB was observed in both normal mucosa and tumor tissues of HAI-1-deficient ApcMin/+ intestines, and an NF-κB target gene, such as urokinase-type plasminogen activator, was upregulated in the HAI-1-deficient tumor tissues. Thus, we investigated the effect of dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic inhibitor of NF-κB, on intestinal HAI-1-deficient ApcMin/+ mice. Treatment with DHMEQ reduced the formation of intestinal tumors compared with vehicle control in the HAI-1-deficient ApcMin/+ mice. These results suggested that insufficient HAI-1 function promotes intestinal carcinogenesis by activating NF-κB signaling.

Topics: Adenomatous Polyposis Coli; Animals; Benzamides; Cell Transformation, Neoplastic; Cyclohexanones; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; Membrane Glycoproteins; Mice, Knockout; Mice, Transgenic; Neoplasms; NF-kappa B; Proteinase Inhibitory Proteins, Secretory; Signal Transduction

The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-kappaB activity driven by IkappaB kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-kappaB during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-kappaB inhibitors.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzamides; Camptothecin; Cell Line, Tumor; Cyclohexanones; Drug Resistance, Neoplasm; Humans; Neoplasms; NF-kappa B; Oncogenes