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ABSTRACT: An 80-year-old woman, who had been administered α-glucosidase inhibitor for diabetes, was brought to the hospital with the sensation of abdominal fullness and pain. Abdominal computed tomography indicated pneumatosis cystoides intestinalis (PCI) in the small intestinal wall, with free air within the abdomen. A blood examination showed no increases in white blood cells or C-reactive protein level. The patient's condition improved with conservative therapy. PCI with pneumoperitoneum induced by α-glucosidase inhibitor is rare, with only 27 cases (excluding the present case) reported in Japan to date. In PCI with pneumoperitoneum, differentiation from gastrointestinal perforation is important and following the clinical symptoms over time is vital.
Acta medica Okayama 04/2013; 67(2):123-8. · 0.84 Impact Factor
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Toshio Nishikawa,
Munenori Takaoka,
Toshiaki Ohara,
Yasuko Tomono,
Huifang Hao,
Xiaohong Bao,
Takuya Fukazawa,
Zhigang Wang,
Kazufumi Sakurama,
Yasuhiro Fujiwara,
Takayuki Motoki, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Noriaki Tanaka,
Toshiyoshi Fujiwara,
Yoshio Naomoto
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ABSTRACT: Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.
Cancer biology & therapy 01/2013; 14(3). · 2.64 Impact Factor
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ABSTRACT: Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion mono-therapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with anti-angiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human non-small cell carcinoma cell lines A549 and H1299 were used in this study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The anti-tumor effects of iron-depletion and anti-angiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted anti-tumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer. © 2012 Wiley Periodicals, Inc.
International Journal of Cancer 11/2012; · 5.44 Impact Factor
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Eiji Yamada, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Leon Sakuma,
Munenori Takaoka,
Takako Yamada,
Kazuhiro Noma,
Kazufumi Sakurama,
Yasuhiro Fujiwara,
Shunsuke Tanabe,
Takeshi Nagasaka,
Toshiyoshi Fujiwara,
Yoshio Naomoto
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ABSTRACT: BACKGROUND: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed. MATERIALS AND METHODS: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings. RESULTS: The SPE group had a longer operation time (SPE: 560 ± 121 min, control 414 ± 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 ± 5.4% versus 87.5 ± 4.7% at 3 mo, P = 0.017; 97.2 ± 7.5% versus 85.0 ± 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01). CONCLUSIONS: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss.
Journal of Surgical Research 08/2012; · 2.25 Impact Factor
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Ryosuke Yoshida,
Hiroshi Tazawa,
Yuuri Hashimoto,
Shuya Yano,
Teppei Onishi,
Tsuyoshi Sasaki, Yasuhiro Shirakawa,
Hiroyuki Kishimoto,
Futoshi Uno,
Masahiko Nishizaki,
Shunsuke Kagawa,
Toshiyoshi Fujiwara
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ABSTRACT: Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.
Cancer Immunology and Immunotherapy 03/2012; · 3.70 Impact Factor
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Shunsuke Tanabe,
Yoshio Naomoto, Yasuhiro Shirakawa,
Yasuhiro Fujiwara,
Kazufumi Sakurama,
Kazuhiro Noma,
Munenori Takaoka,
Tomoki Yamatsuji,
Takao Hiraki,
Yoshihiro Okumura,
Masahiko Mitani,
Mitsumasa Kaji,
Susumu Kanazawa,
Toshiyoshi Fujiwara
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ABSTRACT: Evaluating the status of disease progression is critical for planning a therapeutic strategy for esophageal cancer. In this regard, F-18 fluorodeoxyglucose-labeled positron emission tomography (PET) is one of the most useful diagnostic modalities. However, there is room to improve its diagnostic performance, such as distinguishing lymph nodal metastases from false positives. In this study, we examined the diagnostic accuracy of fluorodeoxyglucose PET accompanied by computed tomography imaging (PET/CT) to detect regional lymph nodal metastasis from esophageal squamous cell carcinoma (ESCC).
A total of 102 patients diagnosed as ESCC were subjected to this study. These patients had a preoperative PET/CT examination to evaluate the existence of metastasis. The values of maximum standardized uptake value (SUVmax) in primary tumors and in metastasized lymph nodes were measured to analyze their relationship with various clinicopathologic characteristics including the status of tumor cell proliferation, which was assessed by immunohistochemistry for Ki-67.
The SUVmax of the primary tumor was positively correlated with tumor size and vessel invasion, and was positively related with the SUVmax of lymph nodal metastasis, especially in cases of poorly differentiated ESCC. The SUVmax of metastasized lymph nodes was higher in larger-sized metastasized lymph nodes, whereas the Ki-labeling index of lymph nodal metastasis was positively related with the SUVmax per unit area (SUVmax/mm). The diagnostic accuracy of PET/CT (87.3%) was higher than that of conventional CT scans (78.4%).
The improved diagnostic accuracy of PET/CT can be explained by its ability to detect actively progressive metastasis at an early phase regardless of size.
Clinical nuclear medicine 10/2011; 36(10):854-9. · 3.92 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 08/2011; 69 Suppl 6:322-8.
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ABSTRACT: Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.
Cancer Science 07/2011; 102(7):1344-9. · 3.33 Impact Factor
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ABSTRACT: Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of E1 genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.
Expert Review of Anti-infective Therapy 04/2011; 11(4):525-32. · 2.65 Impact Factor
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Takayuki Motoki,
Yoshio Naomoto,
Junji Hoshiba, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Munenori Takaoka,
Yasuko Tomono,
Yasuhiro Fujiwara,
Hiroshi Tsuchita,
Mehmet Gunduz,
Hitoshi Nagatsuka,
Noriaki Tanaka,
Toshiyoshi Fujiwara
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ABSTRACT: To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells.
We developed three kinds of artificial milk with different amounts of glutamine; Complete amino acid milk (CAM), which is based on maternal mouse milk, glutamine-depleted milk (GDM), and glutamine-rich milk (GRM). GRM contains three-fold more glutamine than CAM. Eighty-seven newborn mice were divided into three groups and were fed with either of CAM, GDM, or GRM via a recently improved nipple-bottle system for seven days. After the feeding period, the mice were subjected to macroscopic and microscopic observations by immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 as markers of cell proliferation, and for cleaved-caspase-3 as a marker of apoptosis. Moreover, IEC6 rat intestinal epithelial cells were cultured in different concentrations of glutamine and were subject to a 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate cell proliferation assay, flow cytometry, and western blotting to examine the biological effect of glutamine on cell growth and apoptosis.
During the feeding period, we found colonic hemorrhage in six of 28 GDM-fed mice (21.4%), but not in the GRM-fed mice, with no differences in body weight gain between each group. Microscopic examination showed destruction of microvilli and the disappearance of glycocalyx of the intestinal wall in the colon epithelial tissues taken from GDM-fed mice. Intake of GDM reduced BrdU incorporation (the average percentage of BrdU-positive staining; GRM: 13.8%, CAM: 10.7%, GDM: 1.14%, GRM vs GDM: P < 0.001, CAM vs GDM: P < 0.001) and Ki-67 labeling index (the average percentage of Ki-67-positive staining; GRM: 24.5%, CAM: 22.4% GDM: 19.4%, GRM vs GDM: P = 0.001, CAM vs GDM: P = 0.049), suggesting that glutamine depletion inhibited cell proliferation of intestinal epithelial cells. Glutamine deprivation further caused the deformation of the nuclear membrane and the plasma membrane, accompanied by chromatin degeneration and an absence of fat droplets from the colonic epithelia, indicating that the cells underwent apoptosis. Moreover, immunohistochemical analysis revealed the appearance of cleaved caspase-3 in colonic epithelial cells of GDM-fed mice. Finally, when IEC6 rat intestinal epithelial cells were cultured without glutamine, cell proliferation was significantly suppressed after 24 h (relative cell growth; 4 mmol/L: 100.0% ± 36.1%, 0 mmol/L: 25.3% ± 25.0%, P < 0.05), with severe cellular damage. The cells underwent apoptosis, accompanied by increased cell population in sub-G0 phase (4 mmol/L: 1.68%, 0.4 mmol/L: 1.35%, 0 mmol/L: 5.21%), where dying cells are supposed to accumulate.
Glutamine is an important alimentary component for the maintenance of intestinal mucosa. Glutamine deprivation can cause instability of the intestinal epithelial alignment by increased apoptosis.
World Journal of Gastroenterology 02/2011; 17(6):717-26. · 2.47 Impact Factor
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Shinji Kuroda,
Toshiya Fujiwara, Yasuhiro Shirakawa,
Yasumoto Yamasaki,
Shuya Yano,
Futoshi Uno,
Hiroshi Tazawa,
Yuuri Hashimoto,
Yuichi Watanabe,
Kazuhiro Noma,
Yasuo Urata,
Shunsuke Kagawa,
Toshiyoshi Fujiwara
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ABSTRACT: The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
Cancer Research 11/2010; 70(22):9339-48. · 7.86 Impact Factor
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Ryotaro Sonoda,
Yoshio Naomoto, Yasuhiro Shirakawa,
Yasuhiro Fujiwara,
Tomoki Yamatsuji,
Kazuhiro Noma,
Shunsuke Tanabe,
Munenori Takaoka,
Mehmet Gunduz,
Hidetsugu Tsujigiwa,
Hitoshi Nagatsuka,
Nobuya Ohara,
Tadashi Yoshino,
Kaiyo Takubo,
Michael Vieth,
Noriaki Tanaka
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ABSTRACT: Sonoda R, Naomoto Y, Shirakawa Y, Fujiwara Y, Yamatsuji T, Noma K, Tanabe S, Takaoka M, Gunduz M, Tsujigiwa H, Nagatsuka H, Ohara N, Yoshino T, Takubo K, Vieth M & Tanaka N (2010) Histopathology 57, 90–100 Preferential up-regulation of heparanase and cyclooxygenase-2 in carcinogenesis of Barrett’s oesophagus and intestinal-type gastric carcinomaAims: Metaplastic changes secondary to chronic inflammation at the gastro–oesophageal junction and at the pyloric antrum are recognized as the premalignant conditions of Barrett’s oesophageal adenocarcinoma and intestinal-type gastric carcinoma (GC), respectively. Heparanase (HPSE) and cyclooxygenase (COX)-2 have been proved to play critical roles in inflammation as well as in cancer. The aim was to examine the meaning of their expression in inflammation-related carcinogenesis.Methods and results: First, expression of HPSE and COX-2 in 78 clinical tissues of Barrett’s oesophagus was examined by immunohistochemistry and in situ hybridization. Their expression was increased during the metaplasia–dysplasia sequence with increased neovascularization. Successively, their expression in Barrett’s dysplasia was compared with that of GC (22 cases of diffuse-type and 10 of intestinal-type). Interestingly, the expression pattern in Barrett’s dysplasia was similar to that in intestinal-type GC, which mainly arises from chronic inflammation. Furthermore, cultured cell lines isolated from differentiated GC tissues, which are often found to be of intestinal-type, revealed up-regulated mRNA expression of HPSE and COX-2.Conclusions: HPSE and COX-2 are preferentially up-regulated in Barrett’s oesophagus and intestinal-type GC. These molecules may play an important role during the development of inflammation-related adenocarcinoma of the upper gastrointestinal tract.
Histopathology 07/2010; 57(1):90 - 100. · 3.08 Impact Factor
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Ryotaro Sonoda,
Yoshio Naomoto, Yasuhiro Shirakawa,
Yasuhiro Fujiwara,
Tomoki Yamatsuji,
Kazuhiro Noma,
Shunsuke Tanabe,
Munenori Takaoka,
Mehmet Gunduz,
Hidetsugu Tsujigiwa,
Hitoshi Nagatsuka,
Nobuya Ohara,
Tadashi Yoshino,
Kaiyo Takubo,
Michael Vieth,
Noriaki Tanaka
[show abstract]
[hide abstract]
ABSTRACT: Metaplastic changes secondary to chronic inflammation at the gastro-oesophageal junction and at the pyloric antrum are recognized as the premalignant conditions of Barrett's oesophageal adenocarcinoma and intestinal-type gastric carcinoma (GC), respectively. Heparanase (HPSE) and cyclooxygenase (COX)-2 have been proved to play critical roles in inflammation as well as in cancer. The aim was to examine the meaning of their expression in inflammation-related carcinogenesis.
First, expression of HPSE and COX-2 in 78 clinical tissues of Barrett's oesophagus was examined by immunohistochemistry and in situ hybridization. Their expression was increased during the metaplasia-dysplasia sequence with increased neovascularization. Successively, their expression in Barrett's dysplasia was compared with that of GC (22 cases of diffuse-type and 10 of intestinal-type). Interestingly, the expression pattern in Barrett's dysplasia was similar to that in intestinal-type GC, which mainly arises from chronic inflammation. Furthermore, cultured cell lines isolated from differentiated GC tissues, which are often found to be of intestinal-type, revealed up-regulated mRNA expression of HPSE and COX-2.
HPSE and COX-2 are preferentially up-regulated in Barrett's oesophagus and intestinal-type GC. These molecules may play an important role during the development of inflammation-related adenocarcinoma of the upper gastrointestinal tract.
Histopathology 07/2010; 57(1):90-100. · 3.08 Impact Factor
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Huifang Hao,
Yoshio Naomoto,
Xiaohong Bao,
Nobuyuki Watanabe,
Kazufumi Sakurama,
Kazuhiro Noma,
Takayuki Motoki,
Yasuko Tomono,
Takuya Fukazawa, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Munenori Takaoka
[show abstract]
[hide abstract]
ABSTRACT: The HSP90 molecular chaperone family is highly conserved and expressed in various organisms ranging from prokaryotes to eukaryotes. HSP90 proteins play essential housekeeping functions, such as controlling the activity, turnover and trafficking of various proteins, promoting cell survival through maintaining the structural and functional integrity of some client proteins which control cell survival, proliferation and apoptosis, and play an important role in the progression of malignant disease. HSP90 proteins are ATP-dependent chaperones and the binding and hydrolysis of ATP are coupled to conformation changes of HSP90, which facilitate client protein folding and maturation. Many natural and synthetic molecular compounds have been proposed as promising cancer therapy via disrupting the formation of complex ATP-HSP90-client proteins.
Oncology Reports 06/2010; 23(6):1483-92. · 1.84 Impact Factor
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Zhi Gang Wang,
Takuya Fukazawa,
Toshio Nishikawa,
Nobuyuki Watanabe,
Kazufumi Sakurama,
Takayuki Motoki,
Shinji Hatakeyama,
Osamu Omori,
Toshiaki Ohara,
Shunsuke Tanabe,
Yasuhiro Fujiwara,
Munenori Takaoka, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Noriaki Tanaka,
Yoshio Naomoto
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ABSTRACT: Esophageal cancer is one of the most frequently occurring cancers in the world. Targeting therapy strategy of cancer with specific inhibitors is developing and has showed promising antitumor efficacy. It is known that mTOR is an important controller of cell growth. RAD001 (everolimus) is a specific inhibitor of mTOR that can block the mTOR signaling pathway. The purposes of this study was to explore the inhibitory effects of RAD001 on mTOR signaling and the mechanism of cell growth suppression by RAD001. We examined both the expression of mTOR, p70S6K and S6 in SEG-1 esophageal cancer cells and KOB-13 normal esophageal epithelial cells and the efficacy of RAD001 against SEG-1 esophageal cancer cells. mTOR, p70S6K and S6 were overexpressed in SEG-1 esophageal cancer cells compared with KOB-13 normal esophageal epithelial cells. SEG-1 esophageal cancer cells were sensitive to RAD001. The survival rate of the cells treated with RAD001 over 0.33 microM was significantly different compared with that of control (P<0.01). RAD001 inhibited the phosphorylation of mTOR (Ser2448) and S6 (Ser240/244) in different grades and the expressions of mTOR, p70S6K and S6. As a result, RAD001 induced a dose-dependent decrease in cell proliferation, G1/S arrest and damage of cell shape. Taken together, these data showed that RAD001 can inhibit mTOR signaling and proliferation in SEG-1 esophageal cancer cells in vitro. It offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer.
Oncology Reports 04/2010; 23(4):1167-72. · 1.84 Impact Factor
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Xiao Hong Bao,
Yoshio Naomoto,
Hui Fang Hao,
Nobuyuki Watanabe,
Kazufumi Sakurama,
Kazuhiro Noma,
Takayuki Motoki,
Yasuko Tomono,
Takuya Fukazawa, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Munenori Takaoka
[show abstract]
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ABSTRACT: Autophagy is a cellular lysosomal degradation pathway involved in proteins and organelles recycling for promoting cell survival, development and homeostasis. It is a multistep process and genetic studies have identified many proteins that participate in autophagosome formation and fusion with lysosomes, and various signaling factors that associate with the regulation of autophagy. In general, autophagy acts as a cell protector and its dysfunction is correlated with diverse pathologies, such as neurodegeneration, liver, heart and muscle diseases, cancer, inflammation and ageing. However, its role in cell death increases the complexity of the autophagic degradation system. A broad understanding of autophagy, ranging from detailed processes, including induction, formation and degradation, to function in physiology and pathology, revealed by accumulating studies, may be helpful for formulating therapeutic strategies for autophagy-associated human diseases.
International Journal of Molecular Medicine 04/2010; 25(4):493-503. · 1.98 Impact Factor
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James J Lee,
Mitsuteru Natsuizaka,
Shinya Ohashi,
Gabrielle S Wong,
Munenori Takaoka,
Carmen Z Michaylira,
Daniela Budo,
John W Tobias,
Michiyuki Kanai, Yasuhiro Shirakawa,
Yoshio Naomoto,
Andres J P Klein-Szanto,
Volker H Haase,
Hiroshi Nakagawa
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ABSTRACT: Hypoxia-inducible factors (HIFs), in particular HIF-1alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E(2) (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.
Carcinogenesis 03/2010; 31(3):427-34. · 5.70 Impact Factor
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Toshiaki Ohara,
Munenori Takaoka,
Kazufumi Sakurama,
Kaori Nagaishi,
Haruo Takeda, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Takeshi Nagasaka,
Junji Matsuoka,
Noriaki Tanaka,
Yoshio Naomoto
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ABSTRACT: We established a promising new experimental animal model with an orthotopic xenograft of esophageal cancer that successfully represents poor oral intake, a major clinical feature of esophageal cancer. The advantage of this model is that no surgical technique is required, only the injection of a cell suspension by a needle and syringe via the esophageal lumen from the mouth, which provides a high reproducibility of tumor implantation and a rapid progress of outcome. We propose that this model is useful to study cancer-related outcomes and for developing new therapies for esophageal cancer, and we expect it to make a contribution to clinical practice.
Cancer letters 02/2010; 293(2):207-12. · 4.86 Impact Factor
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Xiao Hong Bao,
Yoshio Naomoto,
Hui Fang Hao,
Nobuyuki Watanabe,
Kazufumi Sakurama,
Kazuhiro Noma,
Takayuki Motoki,
Yasuko Tomono,
Takuya Fukazawa, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Munenori Takaoka
[show abstract]
[hide abstract]
ABSTRACT: The type I insulin-like growth factor receptor (IGF-IR) and its associated signaling system play a significant role in tumorigenesis, tumor survival and progression, and cancer therapeutic resistance, and thus has provoked great interest as a promising target for cancer treatment. In this report we present the role of IGF-IR in gastrointestinal carcinomas whose pathology has been identified as tightly correlated with an abnormal expression and activation of IGF-IR. Reported data from experimental studies suggest the feasibility of targeted IGF-IR therapy in gastrointestinal carcinomas. Many types of inhibitors against IGF-IR have been developed. Inhibitors with anti-IGF-IR monoclonal antibodies and tyrosine kinase inhibitors currently undergoing preclinical and clinical evolution are also reviewed.
Oncology letters 01/2010; 1(1):195-201. · 0.11 Impact Factor
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Hui-Fang Hao,
Yoshio Naomoto,
Xiao-Hong Bao,
Nobuyuki Watanabe,
Kazufumi Sakurama,
Kazuhiro Noma,
Yasuko Tomono,
Takuya Fukazawa, Yasuhiro Shirakawa,
Tomoki Yamatsuji,
Junji Matsuoka,
Munenori Takaoka
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ABSTRACT: Focal adhesion kinase (FAK) is a 125-kDa non-receptor protein tyrosine. Growth factors or the clustering of integrins facilitate the rapid phosphorylation of FAK at Tyr-397 and this in turn recruits Src-family protein tyrosine kinases, resulting in the phosphorylation of Tyr-576 and Tyr-577 in the FAK activation loop and full catalytic FAK activation. FAK plays a critical role in the biological processes of normal and cancer cells including the gastrointestinal tract. FAK also plays an important role in the restitution, cell survival and apoptosis and carcinogenesis of the gastrointestinal tract. FAK is over-expressed in cancer cells and its over-expression and elevated activities are associated with motility and invasion of cancer cells. FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors effectively inhibit the kinase activity of FAK and show a potent inhibitory effect for the proliferation and migration of tumor cells, indicating a high potential for application in cancer therapy.
World Journal of Gastroenterology 12/2009; 15(47):5916-23. · 2.47 Impact Factor
