Satomi Yoneyama

Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation.

BACKGROUND Zoledronic acid (ZOL) is clinically available for the treatment of skeletal complications. In preclinical studies, strong anti-cancer activities against breast cancer, prostate cancer, and leukemia were reported. It also inhibited the proliferation of cultured human endothelial cells, suggestive of an anti-angiogenic activity. Since ZOL has the tendency to accumulate in bone, we investigated the effect of ZOL on endothelial progenitor cells (EPCs), which originate from the bone marrow, and play important roles in angiogenesis. MATERIALS AND METHODS Human peripheral blood mononuclear cells were cultured for 7 d to differentiate into EPCs. Cells were treated without/with ZOL or with geranylgeraniol (GGOH). Their endothelial phenotype was confirmed by the expression of CD144 and vascular endothelial growth factor receptor 2 and the tube-like formation ability on Matrigel (Becton Dickinson, Bedford, MA). Annexin V/propidium iodide staining was used to analyze apoptosis. RESULTS ZOL treatment, even at low doses, from d 2 to 7 of culture resulted in impaired EPC differentiation and could be restored by co-treatment with GGOH. On the other hand, treatment of putative EPCs with ZOL at concentrations higher than 10 mum resulted in induction of apoptosis. CONCLUSION ZOL dose-dependently inhibited the differentiation of EPCs, the effect being observed even at low drug levels. At high concentrations, ZOL also induced the apoptotic death of putative EPCs. Since GGOH restored the inhibitory effect of ZOL on EPCs differentiation, the effect of ZOL appears to be dependent on the inhibition of prenylation of small-G-proteins. From these findings, we conclude that ZOL could be a potential anticancer agent by inhibiting angiogenesis.

Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis

Sulforaphane (SUL), one of the isothiocyanates (ITCs), has recently been focused due to its inhibitory effects on tumor cell growth in vitro and in vivo, which is dependent on the direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of SUL and its mechanism of action. Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of SUL on the various steps of angiogenesis, including the proliferation of endothelial cells, tubular formation, and matrix metalloproteinase (MMP) production. Sulforaphane induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on cell apoptosis. Also SUL inhibited tube formation on matrigel, but did not affect MMP production. The present results demonstrate the anti-angiogenic activity of SUL and its potential use as an anti-cancer drug is suggested.

Targeting Id1 and Id3 inhibits peritoneal metastasis of gastric cancer

Inhibitor of DNA binding (Id) proteins are essential for cell differentiation, proliferation, migration, invasion and angiogenesis. Recently, they have been shown to correlate with less differentiated phenotypes, high malignant potential and poor clinical outcome in various kinds of tumors. In an attempt to develop new strategies for the treatment of peritoneal metastasis of gastric cancer, we prepared an Id1, 3 double‐knockdown gastric cancer cell line, MKN45, by RNA interference and investigated its effects on the development of metastatic nodules in the peritoneal cavity. Both cell proliferation and migration capabilities were decreased in Id1, 3 double‐knockdown cells, as was their ability to bind to laminin, which could be explained by the decreased expression of integrin α6. These are important steps in the metastatic process. In a mouse model, the number of peritoneal metastatic nodules formed by Id1, 3 double‐knockdown cells was reduced compared to mock‐transfected control cells, as was the size of individual tumors. In this study, we clearly demonstrated that Id1, 3 double‐knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis. Id should be considered an ideal target for the treatment and prevention of gastric cancer, and RNA interference is an attractive and promising strategy to achieve it. (Cancer Sci 2005; 96: 784–790)

Plaunotol and Geranylgeraniol Induce Caspase-Mediated Apoptosis in Colon Cancer

BACKGROUND Plaunotol, a kind of isoprenoid extracted from a Thai medical plant, plau-noi, is structurally similar to geranylgeraniol (GGOH), another isoprenoid reported to exert strong anticancer effects. Recently, we have reported on its inhibitory effects on tumor angiogenesis and direct effects on gastric cancer cells. Here, we aimed to test whether plaunotol could have some therapeutic effect on colon cancer. MATERIALS AND METHODS Human colon cancer cell line DLD1 was used. Tumor cells were cultured in the presence of plaunotol or GGOH, and their proliferation was measured by MTS assay. Apoptosis was evaluated by Annexin V and propidium iodide double-staining or terminal-deoxynucleotidyl assay. The activation of caspase-3, -8, and -9 was analyzed by flow cytometry and Western blot analysis for PRRP cleavage. RESULTS Plaunotol and GGOH strongly inhibited the proliferative activity of DLD1, dependent on induction of apoptosis. The induction of apoptosis by either plaunotol or GGOH was dependent on the activation of both caspase-8 and caspase-9 pathways. CONCLUSIONS Plaunotol would be a potential anticancer agent against colon cancer, and since it is already available in Japan and Thailand for clinical use as an anti-ulcer/antigastritis agent, clinical trials will be designed to confirm the present findings.

Adenomyoma of the small intestine in an adult: report of a case.

We report a case of adenomyoma in the small intestine, which is an extremely rare entity. An 81-year-old woman presented to our hospital with a history of three episodes of vomiting accompanied by abdominal pain. Upper gastrointestinal examination via a long tube found intestinal obstruction caused by a tumor of the small intestine. Laparotomy revealed a hard mass, 160 cm distal to the Treitz ligament. Pathological examinations of the resected tumor confi rmed a diagnosis of adenomyoma originating in the small intestine. To our knowledge, this is only the second report of an adenomyoma of small intestine causing intestinal obstruction in an adult.

A case of extraperitoneal stoma-associated internal hernia after abdominoperineal resection

Published reports concerning internal hernias after extraperitoneal stoma construction are scarce. In our present report, we describe the case of a 56-year-old man who was referred to our hospital for the treatment of rectal cancer. He underwent abdominoperineal resection of the rectum with sigmoidostomy using an extraperitoneal route. On the ninth postoperative day, the patient experienced sudden and intense abdominal pain and was diagnosed with strangulation of the small intestine due to a stoma-associated internal hernia. Therefore, an emergency laparotomy was performed. The surgical findings showed that the small intestine protruded through the space between the sigmoid colon loop and the abdominal wall in a cranial-to-caudal direction. The strangulated portion of the small intestine was recovered, and the orifice of herniation was closed. No recurrence of internal herniation was observed during the follow-up period.

Rectovaginal fistula after low anterior resection for rectal cancer healed by nonoperative treatment

Highlights • Rectovaginal fistula (RVF) is one of the complications after low anterior resection for rectal cancer.• RVF has been considered to be refractory to conservative treatment.• We report a case of RVF in which conservative treatment was successful.