Our previous studies have clearly shown that the angiogenic enzymes, matrix metalloproteinase (MMP) -2/9, are directly involved in human hepatic tumorigenesis and metastasis and suggest that the MMP-2/9 inhibitors, which have dual inhibitory activities on enzyme activity and transcription, represent the best candidates for achieving tumor regression. Many anti-cancer drugs have strong cellular cytotoxicity and side effects, indicating that strong anti-cancer drugs that have no or minimal cytotoxicity and side effects need to be developed. The specific aim of the present study was to develop powerful anti-cancer drugs with specific tumor regression and anti-metastatic potential having the dual inhibitory activities of specific MMP-2 and -9 enzyme activities and gene transcription at the molecular level. Caffeic acid (CA), a strong and selective MMP-9 activity and transcription inhibitor, was isolated from the plant Euonymus alatus and its derivative, caffeic acid phenethyl ester (CAPE), was synthesized. CA and CAPE selectively inhibited MMP-2 and -9 but not -1, -3, -7, or cathepsin K. Treatment of HepG2 cells with CA (100 microg/mL) and CAPE (5 microg/mL) suppressed phorbol 12-myristate 13-acetate (PMA) -induced MMP-9 expression by inhibiting the function of NF-kappaB, but not AP-1. We confirmed that CA and CAPE suppressed the growth of HepG2 tumor xenografts in nude mice in vivo. The subcutaneous and oral administrations of CA and CAPE significantly reduced the liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the anti-metastatic and anti-tumor effects of CA and CAPE are mediated through the selective suppression of MMP-9 enzyme activity and transcriptional down-regulation by the dual inhibition of NF-kappaB as well as MMP-9 catalytic activity.

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Surgical excision is the treatment of choice for subungual glomus tumor. However, the anatomical location has inherent difficulties. We report the outcomes of surgical treatments for subungual glomus tumor. Sixteen patients, who were seen over an eight-year period (1995-2003) and confirmed as gloums tumor by histopathologic examination were reviewed. The most common subjective symptom was pain induced by contact in 81%. The tumor presented as a discolorated spot or subungual nodule and 38% of tumors were acccompanied with nail dystrophy. All tumors showed discolorated spots or subungual nodules. As shown in the Table 2, the dystrophic nail change was found in 38% of tumors. Differently oriented incisions were made according to the location of tumor, matrix, or bed. The original nail plate was restored in eight patients. Thirteen patients (81%) had cosmetically excellent nail plates, and three patients (19%) had partial distal splits of nail plates. There was no recurrence. Our series suggests that a transungual approach with nail avulsion and an incision selected according to the tumor location can produce an excellent outcome with minimal postoperative complications. Dressing with a trimmed nail plate may also be beneficial in managing the wound and preventing postoperative nail deformity.

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Citrus fruits are high in naringin, which has a beneficial effect on cardiovascular diseases. However, the matrix metalloproteinase-9 (MMP-9) regulation involved in cell migration and invasion remains to be identified. Naringin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of MMP-9, under 10-25 microM concentration conditions in vascular smooth muscle cells (VSMC). The TNF-alpha-induced invasion and migration of VSMC were inhibited by naringin. Furthermore, naringin suppressed TNF-alpha-mediated release of interleukin-6 and -8 (IL-6 and IL-8). However, naringin (10-25 microM) treatment of VSMC in the presence of TNF-alpha did not affect cell growth and apoptosis. In additional experiments, naringin reduced the transcriptional activity of activator protein-1 and nuclear factor kappaB (NF-kappaB), which are two important nuclear transcription factors that are involved in MMP-9 expression. Also, naringin treatment blocked PI3K/AKT/mTOR/p70S6K pathway in TNF-alpha-induced VSMC. Treatment of aglycone naringenin (10-25 microM) had same effect on the levels of MMP-9 expression, invasion, migration, and AKT phosphorylation in TNF-alpha-induced VSMC, compared with naringin treatment. These results suggest that naringin represses PI3K/AKT/mTOR/p70S6K pathway, invasion and migration, and subsequently suppresses MMP-9 expression through the transcription factors NF-kappaB and activator protein-1 in TNF-alpha-induced VSMC. These novel findings provide a theoretical basis for the preventive use of naringin for atherosclerosis disease.