dehydroxymethylepoxyquinomicin and Neoplasm-Metastasis

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

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