Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review

Abstract

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.

Keywords: 3D cell culture; DHMEQ; adhesion; epoxyqinomicin; invasion; metastasis.

Figure 1

Molecular design of (−)-DHMEQ as an inhibitor of NF-κB based on the structure of antibiotic epoxyquinomicin C.

Figure 2

Synthesis of racemic DHMEQ. Racemic DHMEQ is synthesized from 2,5-dihydroxyaniline in five steps.

Figure 3

(−)-DHMEQ binds to Cys38 in p65. Cysteine residues are shown in red.

Figure 4

Anti-inflammatory and anticancer activities of DHMEQ in animal models.

Figure 5

Several steps of metastasis. The early phase including cell detachment and invasion can be studied by 3D invasion of cultured cells, and later phase including invasion and attachment is commonly studied by injection of cancer cells into the transporting veins in animal experiments.

Figure 6

Inhibition of pancreatic cancer cell metastasis in liver by intraperitoneal administration of DHMEQ in mice.

Figure 7

Time-course of 3D invasion in breast carcinoma MDA-MB-231 cells. (Modified from the figure in Reference 34). The cells were cultured in a 96-well round bottom well. DHMEQ inhibited 3D invasion by the decrease of MMP-2 expression.

Figure 8

DHMEQ inhibits IL-6, MCP-1, and hyaluronan expression in human peritoneal mesothelial cells (HPMC). It also inhibits collagen production in HPMC stimulated by effluent dialysate form continuous ambulatory peritoneal dialysis.

Figure 9

Peritoneal NF-κB may contribute to the progression of peripheral inflammation and cancer.

Figure 10

DHMEQ would inhibit both late and early phases of metastasis.