Touko Inao

Shimane University, Matsu, Shimane, Japan

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Publications (8)32.88 Total impact

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    ABSTRACT: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or Beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability and increasing apoptosis. Based on these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with pifithrin-μ. The combination of TRAIL plus pifithrin-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared to cells treated with either agent alone. When applied alone, pifithrin-μ increased Annexin V+ cells in both caspase-dependent and caspase-independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, pifithrin-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared to treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that pifithrin-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL.
    Molecular Cancer Therapeutics 01/2013; 12(4). DOI:10.1158/1535-7163.MCT-12-0954 · 5.68 Impact Factor
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    ABSTRACT: Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.
    Cancer Immunology and Immunotherapy 08/2012; 62(2). DOI:10.1007/s00262-012-1343-0 · 3.94 Impact Factor
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    ABSTRACT: Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic-polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation-associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase-dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells.
    Breast Cancer Research and Treatment 12/2011; 134(1):89-100. DOI:10.1007/s10549-011-1930-3 · 3.94 Impact Factor
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    ABSTRACT: We assessed the expression of cytokeratin (CK) and apomucin (MUC) in ampullary carcinoma (AC) to develop a system for the classification of ACs on the basis of their clinical significance. We studied the expressions of CK7, CK20, MUC1, MUC2, MUC5AC, and MUC6 in 43 patients with ACs. Clinical data were obtained retrospectively by examining surgically resected ACs of the patients. We classified the cases into 3 groups: tumors expressing CK20 and lacking MUC1 (intestinal type [I-type], 26%), tumors expressing MUC1 and lacking CK20 (pancreatobiliary type [PB-type], 35%), and those expressing or lacking both CK20 and MUC1 (other type [O-type], 39%). Eight (73%) of 11 I-type carcinomas, 3 (20%) of 15 PB-type carcinomas, and 4 (24%) of 17 O-type carcinomas were classified as pT1. The number of I-type carcinomas in the early tumor stages was significantly higher than the number of PB- and O-type carcinomas (p = 0.014 and p = 0.018, respectively). The 5-year survival rates for pT1, pT2, and pT3 tumors were 76%, 33%, and 22%, respectively (p < 0.001). Rates of MUC5AC and MUC6 coexpression for I-type, PB-type, and O-type tumors were 18%, 13%, and 53%, respectively. There was a significant correlation between MUC5AC and MUC6 coexpression and O-type characteristics (p = 0.031). The five-year survival rates for O-type ACs with and without MUC5AC and MUC6 coexpression were 71% and 17%, respectively (p = 0.048). The immunohistochemical subtypes based on CK and MUC expression correlated with tumor progression. Gastric MUC5AC and MUC6 coexpression correlated with better prognosis for O-type ACs.
    Diagnostic Pathology 11/2010; 5(1):75. DOI:10.1186/1746-1596-5-75 · 2.60 Impact Factor
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    ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is reported to complicate malignancies disease in 30% of cases and complicate invasive ductal carcinoma of the pancreas too, but is rare in multiple cancers. We report a patient with IPMN accompanied by triple cancers. The 60-year-old woman had been followed for IPMN for 7 years, during which time she underwent a hysterectomy due to uterine corpus cancer at age 56 and bilateral breast-preserving surgery due to bilateral breast cancer at age 60. During radiation therapy after breast cancer surgery, a tumor was found in the pancreas body in abdominal computed tomography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed the main pancreas duct to be occluded at the body and at the tail to be delated. Cytology of the pancreatic juice was class IV. We diagnosed pancreatic cancer with IPMN and conducted subtotal distal pancreatectomy, without resecting the IPMN, which was considered benign. Physicians should look for malignant disease in patients with IPMN because cancer complications may adversely affect their prognosis.
    Nippon Shokaki Geka Gakkai zasshi 06/2008; 41(6):653-657. DOI:10.5833/jjgs.41.653
  • Gastroenterology 04/2008; 134(4). DOI:10.1016/S0016-5085(08)61250-0 · 16.72 Impact Factor
  • Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association) 01/2007; 68(4):993-997. DOI:10.3919/jjsa.68.993
  • Nippon Shokaki Geka Gakkai zasshi 01/2007; 40(9):1599-1604. DOI:10.5833/jjgs.40.1599