Yoshiharu Motoo

Publications (102)173.69 Total impact

• Article: Significance of kampo, Japanese traditional medicine, in the treatment of obesity: basic and clinical evidence.

  Jun-Ichi Yamakawa, Junji Moriya, Kenji Takeuchi, Mio Nakatou, Yoshiharu Motoo, Junji Kobayashi
  [show abstract] [hide abstract]
  ABSTRACT: The cause of obesity includes genetic and environmental factors, including cytokines derived from adipocytes (adipo-cytokines). Although drug therapy is available for obesity, it is highly risky. Our main focus in this review is on the traditional form of Japanese medicine, Kampo, in the treated of obesity. Two Kampo formulas, that is, bofutsushosan () and boiogito (), are covered by the national health insurance in Japan for the treatment of obesity. Various issues related to their action mechanisms remain unsolved. Considering these, we described the results of basic experiments and presented clinical evidence and case reports on osteoarthritis as examples of clinical application of their two Kampo medicine. Traditional medicine is used not only for treatment but also for prevention. In clinical practice, it is of great importance to prove the efficacy of combinations of traditional medicine and Western medicine and the utility of traditional medicine in the attenuation of adverse effects of Western medicine.
  Evidence-based Complementary and Alternative Medicine 01/2013; 2013:943075. · 4.77 Impact Factor
• Article: Aberrant glycogen synthase kinase 3β is involved in pancreatic cancer cell invasion and resistance to therapy.

  Ayako Kitano, Takeo Shimasaki, Yuri Chikano, Mitsutoshi Nakada, Mayumi Hirose, Tomomi Higashi, Yasuhito Ishigaki, Yoshio Endo, Takahisa Takino, Hiroshi Sato, Yoshimichi Sai, Ken-Ichi Miyamoto, Yoshiharu Motoo, Kazuyuki Kawakami, Toshinari Minamoto
  [show abstract] [hide abstract]
  ABSTRACT: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer. Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined. Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts. The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer.
  PLoS ONE 01/2013; 8(2):e55289. · 4.09 Impact Factor
• Article: Daily 500 mg Valacyclovir Is Effective for Prevention of Varicella Zoster Virus Reactivation in Patients with Multiple Myeloma Treated with Bortezomib.

  Toshihiro Fukushima, Tomomi Sato, Takuji Nakamura, Haruka Iwao, Akio Nakajima, Miyuki Miki, Tomoyuki Sakai, Takafumi Kawanami, Toshioki Sawaki, Yoshimasa Fujita, Masao Tanaka, Yasufumi Masaki, Toshiro Okazaki, Hideo Nakajima, Yoshiharu Motoo, Hisanori Umehara
  [show abstract] [hide abstract]
  ABSTRACT: In patients with multiple myeloma (MM), bortezomib is associated with a significant risk of Varicella zoster virus (VZV) reactivation. There are some reports that acyclovir reduces the risk of VZV reactivation. We assessed whether VZV reactivation could be reduced by using prophylactic valacyclovir at a dose of 500 mg daily. We retrospectively evaluated 32 patients with MM who received bortezomib and valacyclovir prophylaxis at the Kanazawa Medical University Hospital. Patients received valacyclovir prophylaxis orally at a dose of 500 mg daily, without cessation during bortezomib treatment. The median age was 69 years (range=45-90 years). Fifteen patients were male and seventeen were female. The median bortezomib dose was 37.0 mg/m(2) (range=5.2-167.6 mg/m(2)). All patients also received corticosteroids. The median duration of valacyclovir prophylaxis was 301 days (range=24-1206 days) and the median valacyclovir dose was 150.5 g (range=12-603 g). VZV reactivation developed in only one patient during valacyclovir prophylaxis. VZV reactivation did not develop in three patients who had a past history of VZV reactivation without valacyclovir prophylaxis. Adverse events over grade 3 associated with valacyclovir were not observed. Valacyclovir at a dose of 500 mg daily appears to be effective at preventing VZV reactivation and was well-tolerated by patients with MM who received bortezomib.
  Anticancer research 12/2012; 32(12):5437-40. · 1.73 Impact Factor
• Article: Characterization of proteins secreted by pancreatic cancer cells with anticancer drug treatment in vitro.

  Takanobu Takata, Yasuhito Ishigaki, Takeo Shimasaki, Hideyuki Tsuchida, Yoshiharu Motoo, Akio Hayashi, Naohisa Tomosugi
  [show abstract] [hide abstract]
  ABSTRACT: Pancreatic cancer is one of the most lethal cancers, with an incidence equaling mortality. It is a heterogeneous group of neoplasms in which pancreatic ductal adenocarcinoma is most common. Pancreatic cancer cannot be cured even if detected early. When treatment is initiated, a suitable method of administration of anticancer drugs must be chosen. Anticancer drugs kill tumor cells. However, side effects including initiation are problematic in anticancer drug therapy. Improved methods for the diagnosis of side effects of pancreatic cancer by using sensitive and specific tumor markers are highly desirable. Therefore, efficient strategies for biomarker discovery are urgently needed. Here, we present an approach based on direct experimental access to proteins released by PANC-1 human pancreatic cancer cells in vitro. A two-dimensional (2-D) map and catalog of this subproteome, herein termed the secretome, were established comprising more than 1,000 proteins observed by '2-D difference in-gel electrophoresis analysis using cyanine dye'. We investigated 22 spots that were 1.20-fold upregulated and 31 spots that were 0.66-fold downregulated by gemcitabine chloride treatment. Proteins in these spots were identified by nano-high-performance liquid chromatography electrospray ionization time of flight mass spectrometry/mass spectrometry. Most secretome constituents were nominally cellular proteins. By mass spectrometry screening, 14-3-3 protein sigma (14-3-3 σ), protein S100-A8, protein S100-A9, galectin-7, lactotransferrin (lactoferrin, LF) precursor, serotransferrin (transferrin) precursor, and vitamin D binding protein precursor were identified. Western blotting confirmed the presence of 14-3-3 σ and LF. We found that upregulation of 14-3-3 σ was associated with apoptosis, and downregulation of LF was found to suppress tumorigenesis.
  Oncology Reports 09/2012; 28(6):1968-76. · 1.84 Impact Factor
• Article: Loss of HITS (FAM107B) expression in cancers of multiple organs: tissue microarray analysis.

  Hideo Nakajima, Keita Koizumi, Takuji Tanaka, Yasuhito Ishigaki, Yoshino Yoshitake, Hideto Yonekura, Tsutomu Sakuma, Toshihiro Fukushima, Hisanori Umehara, Soichiro Ueno, Toshinari Minamoto, Yoshiharu Motoo
  [show abstract] [hide abstract]
  ABSTRACT: Family with sequence similarity 107 (FAM107) proteins consist of two subtypes, FAM107A and FAM107B in mammals, possessing a conserved N-terminal domain of unknown function. Recently we found that FAM107B, an 18 kDa nuclear protein, is expressed in a broad range of tissues and is downregulated in gastrointestinal cancer. Because FAM107B expression is amplified by heat-shock stimulation, we designated it heat shock-inducible tumor small protein (HITS). Although data related to FAM107A as a candidate tumor suppressor have been accumulated, little biological information is available for HITS. In the present study, we examined HITS expression using immunohistochemistry with tissue microarrays and performed detailed statistical analyses. By screening a high-density multiple organ tumor and normal tissue microarray, HITS expression was decreased in tumor tissues of the breast, thyroid, testis and uterine cervix as well as the stomach and colon. Further analysis of tissue microarrays of individual organs showed that loss of HITS expression in cancer tissues was statistically significant and commonly observed in distinct organs in a histological type-specific manner. The HITS expression intensity was inversely correlated with the primary tumor size in breast and thyroid cancers. In addition, effects of tetracycline-inducible HITS expression on tumor growth were investigated in vivo. Forced expression of HITS inhibited tumor xenograft proliferation, compared with the mock-treated tumor xenograft model. These results show that loss of HITS expression is a common phenomenon observed in cancers of distinct organs and involved in tumor development and proliferation.
  International Journal of Oncology 07/2012; · 2.40 Impact Factor
• Article: Effect of herbal medicine Saiko-Keishi-to (TJ-10) on rat spontaneous chronic pancreatitis

  Yoshiharu Motoo, Shi-Bing Su, Min-Jue Xie, Hiromi Taga, Norio Sawabu
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  ABSTRACT: Background. In an attempt to obtain evidence of the beneficial effects of TJ-10, we investigated the gene expression of PAP, an acute phase protein specific for pancreatitis in rat spontaneous chronic pancreatitis. Methods. Four-wk-old male WBN/Kob rats were fed with MB-3 pellet diet containing herbal medicine. There were two administration groups for each drug: the prophylactic group administered from 4–12 wk, and the therapeutic group administered from 12–20 wk. Untreated control rats were fed with MB-3 alone. Histopathologic changes and PAP gene expressions were analyzed at 12 and 20 wk. Results. In the prophylactic group, TJ-10-treated WBN/Kob rats showed no evidence of pancreatitis, and there was the amelioration of pancreatitis in the pancreata of the rats treated with other herbal medicines except TJ-24 at 12 wk. PAP mRNA was not expressed in the TJ-10-treated rats, and PAP gene expression was suppressed in rats treated with other drugs except TJ-107. In the therapeutic group, the amelioration of pancreatitis was seen only in TJ-10-treated rats, but PAP gene expression was significantly suppressed in the rats treated with all herbal medicines tested, compared with that in untreated control rats. Conclusion. An herbal medicine Saiko-keishi-to (TJ-10) delayed the onset of chronic pancreatitis in the WBN/Kob rat, and suppressed the pancreatitis-associated protein (PAP) gene expression more significantly than other herbal medicines.
  International Journal of Gastrointestinal Cancer 04/2012; 27(2):123-129.
• Article: Prediction of docetaxel monotherapy-induced neutropenia based on the monocyte percentage.

  Itaru Sato, Naoki Nakaya, Takeo Shimasaki, Hideo Nakajima, Yoshiharu Motoo
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  ABSTRACT: We retrospectively reviewed the medical records of 32 chemonaïve patients with either breast, lung or prostate cancer, who were treated with docetaxel (DOC) monotherapy, and evaluated whether the proportion of peripheral blood monocytes was capable of predicting the occurrence of neutropenia following chemotherapy. In the granulocyte-colony stimulating factor (G-CSF) non‑administration group, the monocyte percentage was inversely correlated with the decrease in neutrophils (P=0.01; corrected correlation coefficient, -0.71). The neutrophil count decreased by ≥30% in 7 of 8 patients with <5% monocytes, whereas it decreased by >30% in 1 of 6 patients with ≥5% monocytes (P=0.01). Three of 8 patients with <5% monocytes experienced grade 4 neutropenia, while in the group with ≥5% monocytes, 1 of 6 patients experienced grade 4 neutropenia. The frequency of grade 3 or 4 neutropenia was lower in patients with ≥5% monocytes than in patients with <5% monocytes, but the difference was not significant (P=0.41). Following G-CSF administration, grade 3 or 4 neutropenia had the tendency of lasting longer in patients with <5% monocytes than in those with ≥5% monocytes; however, the monocyte percentage was not correlated with the grade of neutropenia (P=0.34). The monocyte percentage following chemotherapy was inversely correlated with the decrease in neutrophils. The percentage of monocytes that are available in clinical practice may be predictive of neutropenia following chemotherapy. Our findings suggest that patients with <5% monocytes following DOC monotherapy are at risk of severe neutropenia and should be carefully monitored.
  Oncology letters 04/2012; 3(4):860-864. · 0.11 Impact Factor
• Source

  Available from: InTech

  Chapter: Distinct Pathologic Roles for Glycogen Synthase Kinase 3? in Colorectal Cancer Progression

  Toshinari Minamoto, Masanori Kotake Mitsutoshi Nakada, Takeo Shimasaki, Yoshiharu Motoo, Kazuyuki Kawakami
  02/2012; , ISBN: 978-953-51-0062-1
• Article: Aberrant glycogen synthase kinase 3β in the development of pancreatic cancer.

  Takeo Shimasaki, Ayako Kitano, Yoshiharu Motoo, Toshinari Minamoto
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  ABSTRACT: Development and progression of pancreatic cancer involves general metabolic disorder, local chronic inflammation, and multistep activation of distinct oncogenic molecular pathways. These pathologic processes result in a highly invasive and metastatic tumor phenotype that is a major obstacle to curative surgical intervention, infusional gemcitabine-based chemotherapy, and radiation therapy. Many clinical trials with chemical compounds and therapeutic antibodies targeting growth factors, angiogenic factors, and matrix metalloproteinases have failed to demonstrate definitive therapeutic benefits to refractory pancreatic cancer patients. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target in common chronic and progressive diseases, including cancer. Here we review accumulating evidence for a pathologic role of GSK3β in promoting tumor cell survival, proliferation, invasion, and resistance to chemotherapy and radiation in pancreatic cancer. We also discuss the putative involvement of GSK3β in mediating metabolic disorder, local inflammation, and molecular alteration leading to pancreatic cancer development. Taken together, we highlight potential therapeutic as well as preventive effects of GSK3β inhibition in pancreatic cancer.
  Journal of Carcinogenesis 01/2012; 11:15.
• Chapter: Stress Responses of Pancreatic Cancer Cells and Their Significance in Invasion and Metastasis

  Yoshiharu Motoo, Qi-Sheng Xia, Naoki Nakaya, Takeo Shimasaki, Hideo Nakajima, Yasuhito Ishigaki
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  ABSTRACT: Stress responses of pancreatic cancer cells are detected in case of ­chemotherapy. We have reported the expression of various stress proteins in ­pancreatic cancer cells with special reference to tumor aggressiveness. Here, we elucidated a previously unknown function of SMG-1, one of PI3 kinases, in the signal transduction of stress responses. Gemcitabine induces epithelial–mesenchymal transition (EMT), producing EMT-inducing factors. Regulation of stress responses might lead to the control of metastasis and the overcome of drug resistance in ­pancreatic cancer.
  12/2011: pages 213-217;
• Article: Glycogen synthase kinase 3β inhibition sensitizes pancreatic cancer cells to gemcitabine.

  Takeo Shimasaki, Yasuhito Ishigaki, Yuka Nakamura, Takanobu Takata, Naoki Nakaya, Hideo Nakajima, Itaru Sato, Xia Zhao, Ayako Kitano, Kazuyuki Kawakami, Takuji Tanaka, Tsutomu Takegami, Naohisa Tomosugi, Toshinari Minamoto, Yoshiharu Motoo
  [show abstract] [hide abstract]
  ABSTRACT: Pancreatic cancer is obstinate and resistant to gemcitabine, a standard chemotherapeutic agent for the disease. We previously showed a therapeutic effect of glycogen synthase kinase-3β (GSK3β) inhibition against gastrointestinal cancer and glioblastoma. Here, we investigated the effect of GSK3β inhibition on pancreatic cancer cell sensitivity to gemcitabine and the underlying molecular mechanism. Expression, phosphorylation, and activity of GSK3β in pancreatic cancer cells (PANC-1) were examined by Western immunoblotting and in vitro kinase assay. The combined effect of gemcitabine and a GSK3β inhibitor (AR-A014418) against PANC-1 cells was examined by isobologram and PANC-1 xenografts in mice. Changes in gene expression in PANC-1 cells following GSK3β inhibition were studied by cDNA microarray and reverse transcription (RT)-PCR. PANC-1 cells showed increased GSK3β expression, phosphorylation at tyrosine 216 (active form), and activity compared with non-neoplastic HEK293 cells. Administration of AR-A014418 at pharmacological doses attenuated proliferation of PANC-1 cells and xenografts, and significantly sensitized them to gemcitabine. Isobologram analysis determined that the combined effect was synergistic. DNA microarray analysis detected GSK3β inhibition-associated changes in gene expression in gemcitabine-treated PANC-1 cells. Among these changes, RT-PCR and Western blotting showed that expression of tumor protein 53-induced nuclear protein 1, a gene regulating cell death and DNA repair, was increased by gemcitabine treatment and substantially decreased by GSK3β inhibition. The results indicate that GSK3β inhibition sensitizes pancreatic cancer cells to gemcitabine with altered expression of genes involved in DNA repair. This study provides insight into the molecular mechanism of gemcitabine resistance and thus a new strategy for pancreatic cancer chemotherapy.
  Journal of Gastroenterology 11/2011; 47(3):321-33. · 4.16 Impact Factor
• Article: [A case of primary cardiac angiosarcoma associated with cardiac tamponade].

  Naoki Nakaya, Itaru Sato, Takeo Shimasaki, Hideo Nakajima, Nozomu Kurose, Takayuki Nojima, Yoshiharu Motoo
  [show abstract] [hide abstract]
  ABSTRACT: A 72-year-old man came to our hospital due to edema, malaise, and poor appetite in May 200X. He was diagnosed as cardiac tamponade, and open surgery revealed tumors in the right atrium and the left ventricule. Tumor tissue was revealed to be angiosarcoma by the pathological findings. Metastases to the brain, lungs, liver, and adrenal glands were found. The patient was treated with interleukin-2(IL-2)for 7 weeks. However, there was no anti-tumor effect, and the patient died in September, 200X. We reported a very rare case of cardiac angiosarcoma associated with cardiac tamponade, who was treated with IL-2 monotherapy.
  Gan to kagaku ryoho. Cancer & chemotherapy 08/2011; 38(8):1353-5.
• Article: Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events.

  Toshihiro Fukushima, Takuji Nakamura, Haruka Iwao, Akio Nakajima, Miyuki Miki, Tomomi Sato, Tomoyuki Sakai, Toshioki Sawaki, Yoshimasa Fujita, Masao Tanaka, Yasufumi Masaki, Hideo Nakajima, Yoshiharu Motoo, Hisanori Umehara
  [show abstract] [hide abstract]
  ABSTRACT: To establish the clinical use of bortezomib with fewer adverse events, we retrospectively analyzed the efficacy and safety of bortezomib plus dexamethasone (BD) therapy for relapsed or refractory multiple myeloma. Patients received bortezomib (1.3 mg/m2) as an intravenous bolus on days 1, 4, 8 and 11 in a 3-week cycle (twice-weekly administration), or on days 1, 8, 15 and 22 in a 5-week cycle (once-weekly administration). Dexamethasone (20 mg) was given on the day of and day after bortezomib treatment. From January 2007 to July 2010, 22 patients began to receive BD therapy. Initially, bortezomib was administered twice-weekly, but some severe adverse events developed; therefore, from January 2008, bortezomib was administered twice-weekly for the first two courses, followed by once-weekly for the subsequent courses. Patients who were expected to have severe adverse events beforehand were treated initially with once-weekly administration. Of the 22 patients, 14 were treated with twice-weekly followed by once-weekly administration, five with only twice-weekly administration and three with only once-weekly administration. Seventeen patients (77.3%) achieved at least partial response, including three with complete response and seven with very good partial response. The median progression-free survival and the median overall survival of 22 patients were 512 days and not reached, respectively. The median progression-free survival and the median overall survival of 17 patients who received at least one course of once-weekly administration were 615 days and not reached, respectively. The most frequent ≥grade 3 adverse events with twice-weekly administration were gastrointestinal, especially paralytic ileus and constipation. Among seven patients who developed ≥grade 3 gastrointestinal adverse events with twice-weekly administration, all four patients changed the schedule to once-weekly were able to continue BD therapy. Once-weekly administration of bortezomib in BD therapy may reduce the incidence of gastrointestinal adverse events without reducing the clinical efficacy of this therapy for refractory or relapsed multiple myeloma.
  Anticancer research 06/2011; 31(6):2297-302. · 1.73 Impact Factor
• Article: [Chemotherapy for urological cancer : usefulness and feasibility of current protocols].

  Isao Hara, Yoshiharu Motoo
  [show abstract] [hide abstract]
  ABSTRACT: In this symposium, we discussed the usefulness and feasibility of current chemotherapy protocols for urological cancers including renal cell carcinoma, urothelial cancer, prostate cancer and testicular cancer. (1) Renal cell carcinoma : Although molecular targeted therapy is now becoming a standard therapy for metastatic renal cell carcinoma, the current situation is somehow confusing due to unknown adverse effects and lack of guidelines for indication of each compound. (2) Urothelial cancer : gemcitabine and cisplatin (GC) therapy is taking over methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) therapy because of less toxicity. We focused on a novel biomarker, hENT1, to predict the anti tumor effect of GC therapy. (3)Prostate cancer : The survival benefit of docetaxel for castration resistant prostate cancer was proven by large clinical trials. We dealt with uracil and tegafur (UFT) therapy which has been widely used in Japan. (4)Testicular cancer : It is needles to say that BEP therapy was established as a standard induction therapy for metastatic testicular cancer. However, regarding salvage chemotherapy, it is still controversial whether vinblastine, ifosphamide and platinum (VIP), paclitaxel, ifosphamide and platinum (TIP) and high dose chemotherapy should be selected.
  Hinyokika kiyo. Acta urologica Japonica 03/2011; 57(3):151-2.
• Article: [Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer].

  Takeo Shimasaki, Katsuhito Miyazawa, Manabu Moriyama, Tatsuro Tanaka, Itaru Sato, Naoki Nakaya, Hideo Nakajima, Anna Kubo, Koji Suzuki, Yoshiharu Motoo
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  ABSTRACT: Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.
  Hinyokika kiyo. Acta urologica Japonica 03/2011; 57(3):163-6.
• Article: Scanning electron microscopy with an ionic liquid reveals the loss of mitotic protrusions of cells during the epithelial-mesenchymal transition.

  Yasuhito Ishigaki, Yuka Nakamura, Teruaki Takehara, Takeo Shimasaki, Takanori Tatsuno, Fumihide Takano, Yoshimichi Ueda, Yoshiharu Motoo, Tsutomu Takegami, Hideaki Nakagawa, Susumu Kuwabata, Noriko Nemoto, Naohisa Tomosugi, Shichiro Miyazawa
  [show abstract] [hide abstract]
  ABSTRACT: Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis and is characterized by increase in cell motility, increase in expression of mesenchymal cell markers, loss of proteins from cell-to-cell junction complexes, and changes in cell morphology. Here, the morphological effects of a representative EMT inducer, transforming growth factor (TGF)-β1, were investigated in human lung adenocarcinoma (A549) cells and pancreatic carcinoma (Panc-1) cells. TGF-β1 caused morphological changes characteristic of EMT, and immunostaining showed loss of E-cadherin from cell-to-cell junction complexes in addition to the upregulation of the mesenchymal marker vimentin. During scanning electron microscopy (SEM) with an ionic liquid, we observed EMT-specific morphological changes, including the formation of various cell protrusions. Interestingly, filopodia in mitotic cells were clearly observed by SEM, and the number of these filopodia in TFG-β1-treated mitotic cells was reduced significantly. We conclude that this reduction in such mitotic protrusions is a novel effect of TGF-β1 and may contribute to EMT.
  Microscopy Research and Technique 03/2011; 74(11):1024-31. · 1.79 Impact Factor
• Article: Traditional Japanese medicine, Kampo: its history and current status.

  Yoshiharu Motoo, Takashi Seki, Kiichiro Tsutani
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  ABSTRACT: Traditional Japanese medicine, Kampo, is used by over 80% of medical doctors in Japan. Owing to its high quality and safety, Kampo has been integrated into modern medicine, and there are 345 randomized controlled trials using Kampo in Japan as of 2010. Although there are a number of articles in top journals about basic science research, we can find only small numbers of high-quality clinical evidence. Since undergraduate education on Kampo has been established, integrative approach with the balanced combination of modern medicine and Kampo is expected to generate good clinical evidence in the near future.
  Chinese Journal of Integrative Medicine 02/2011; 17(2):85-7. · 0.80 Impact Factor
• Article: Human SMG-1 is involved in gemcitabine-induced primary microRNA-155/BIC up-regulation in human pancreatic cancer PANC-1 cells.

  Qi-sheng Xia, Yasuhito Ishigaki, Xia Zhao, Takeo Shimasaki, Hideo Nakajima, Hideaki Nakagawa, Tsutomu Takegami, Zhi-hua Chen, Yoshiharu Motoo
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  ABSTRACT: Human primary microRNA-155/B-cell integration cluster (BIC) transcript is the precursor of microRNA-155. The overexpression of them has been widely observed in the progression of various types of tumors. Our objective was to investigate the effect of anticancer agents on the expression of BIC and possible signal pathways that involved in. Quantitative real-time reverse transcriptase polymerase chain reaction was used to measure the expression of BIC. Chemical inhibitors against c-Jun N-terminal kinase 1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2, protein kinase C, checkpoint kinase 1, and phosphatidylinositol 3 kinase (PI3K) were used for the evaluation of involved signal pathways. RNA interference was used to knock down the expression of ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3 related, and suppressor of morphogenesis in genitalia-1 (SMG-1), and Western blot was carried out to evaluate the knockdown effect. B-cell integration cluster expression was induced by a representative anti-pancreatic cancer drug, gemcitabine, in human pancreatic cancer PANC-1 cells. The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and c-Jun N-terminal kinase inhibitors, but not the checkpoint kinase 1 and protein kinase C inhibitors, suppressed the up-regulation of BIC. B-cell integration cluster up-regulation was also significantly inhibited by the PI3K inhibitor wortmannin. RNA interference studies showed that wortmannin-sensitive SMG-1 but not ataxia-telangiectasia mutated or ataxia-telangiectasia and Rad3 related was involved in the up-regulation. Our results show that multiple pathways can be involved in the up-regulation of BIC. Furthermore, we demonstrate for the first time that PI3K SMG-1 is required for gemcitabine-induced up-regulation of BIC transcript.
  Pancreas 01/2011; 40(1):55-60. · 2.39 Impact Factor
• Article: Cost-effectiveness analysis of KRAS testing and cetuximab as last-line therapy for colorectal cancer.

  Takeru Shiroiwa, Yoshiharu Motoo, Kiichiro Tsutani
  [show abstract] [hide abstract]
  ABSTRACT: Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves progression-free survival and overall survival in patients with metastatic colorectal cancer (mCRC). However, patients with a KRAS gene mutation do not benefit from cetuximab therapy. We performed a cost-effectiveness analysis of KRAS testing and cetuximab treatment as last-line therapy for patients with mCRC in Japan. In our analysis, we considered three treatment strategies. In the 'KRAS-testing strategy' (strategy A), KRAS testing was performed to guide treatment: patients with wild-type KRAS received cetuximab, and those with mutant KRAS received best supportive care (BSC). In the 'no-KRAS-testing strategy' (strategy B), genetic testing was not conducted and all patients received cetuximab. In the 'no-cetuximab strategy' (strategy C), genetic testing was not conducted and all patients received BSC. To evaluate the cost effectiveness of KRAS testing, the KRAS-testing strategy was compared with the no-KRAS-testing strategy; to evaluate the cost effectiveness of KRAS testing and cetuximab, the KRAS-testing strategy was compared with the no-cetuximab strategy; and to evaluate the cost effectiveness of cetuximab treatment without KRAS testing, the no-KRAS-testing strategy was compared with the no-cetuximab strategy. A three-state Markov model was used to predict expected costs and outcomes for each group. Outcomes in the model were based on those reported in a retrospective analysis of data from the National Cancer Institute of Canada Clinical Trials Group CO.17 study. We included only direct medical costs from the perspective of the Japanese healthcare payer. A 3% discount rate was used for both costs and outcome. Two outcomes, life-years (LYs) gained and quality-adjusted life-years (QALYs) gained, were used to calculate the incremental cost-effectiveness ratio (ICER). Our cost-effectiveness analysis revealed that the KRAS-testing strategy was dominant compared with the no-KRAS-testing strategy, with an expected cost reduction of ¥0.5 million per patient and an estimated budget impact of ¥3-5 billion ($US42-59 million; July 2010 values) per year. The ICER of the KRAS-testing strategy compared with the no-cetuximab strategy was ¥11 million ($US120 000) per LY gained and ¥16 million ($US160 000) per QALY gained, whereas the ICER of the KRAS-testing strategy compared with the no-KRAS-testing strategy was ¥14 million ($US180 000) per LY gained and ¥21 million ($US230 000) per QALY gained. These results were supported by the sensitivity analysis. KRAS testing is recommended before administering cetuximab as last-line therapy for patients with mCRC. However, our analysis suggests that the ICER of cetuximab treatment (with or without KRAS testing) is too high, even if treatment is limited to patients with wild-type KRAS.
  Molecular diagnosis & therapy 12/2010; 14(6):375-84. · 1.71 Impact Factor
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  Available from: cellbiolint.org

  Article: Multiple factors influencing the release of hTERT mRNA from pancreatic cancer cell lines in in vitro culture.

  Gensaku Okada, Hiroyuki Watanabe, Koushiro Ohtsubo, Hisatsugu Mouri, Yasushi Yamaguchi, Yoshiharu Motoo, Norio Sawabu
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  ABSTRACT: Since telomerase expression is highly prevalent in human cancers, the quantitation of serum/plasma hTERT (human telomerase reverse transcriptase) mRNA levels may be useful for early detection of PCa (pancreatic cancer). To analyse the correspondence between exhTERT (extracellular hTERT) mRNA levels and hTERT expression, we designed a cell culture system to investigate factors modulating the extracellular levels of hTERT mRNA in media conditioned by eight PCa cell lines. We found that the level of exhTERT mRNA was dependent on cell growth rate. MIAPaCa-2, PANC-1, KLM-1 and PK-9 cells expressed high levels of exhTERT mRNA, independent of cell density, whereas proliferating PK-59, BxPC-3 and PK-45H cells released low levels of exhTERT mRNA. The augmented release of mRNA by spontaneous dead MIAPaCa-2 cells was further increased at postconfluence. In Capan-1 cells, low correspondence of marker was also due to RNase secretion. Upon reaching confluence, some PCa cell lines showed down-regulation of hTERT expression. Following cell-cell adhesion, as shown by E-cadherin engagement, PK-59 cells showed levels of extracellular message below the limits of detection, a loss not due to an increase in message degradation. These results suggest that the levels of exhTERT mRNA in the medium of PCa cell lines are altered not only in response to cell growth rate and cell destruction, but are responsive to extracellular cues such as RNases and cell density. A cell-free assay for exhTERT mRNA may therefore not be useful for early detection of PCa.
  Cell Biology International 11/2010; 36(6):545-53. · 1.48 Impact Factor