Yukimasa Shiotsu

Kyowa Hakko Kirin, Edo, Tōkyō, Japan

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Publications (27)133.97 Total impact

  • Shiro Soga, Shiro Akinaga, Yukimasa Shiotsu
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    ABSTRACT: Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone which stabilizes various oncogenic kinases, including HER2, EGFR, BCR-ABL, B-Raf and EML4-ALK, which are essential for tumor growth. Several monoclonal antibodies and small molecule kinase inhibitors which target these kinases have been identified as potential new molecular target therapeutics. Previous reports have shown that many oncogenic proteins essential for cancer transformation are chaperoned by the Hsp90 complex, and some of these client proteins have been discovered by using Hsp90 inhibitors, such as geldanamycin (GA) and radicicol (RD).Thus far more than 200 client proteins have been identified. In past derivatives of these natural products have been evaluated in clinical trials, but none of the 1st generation of Hsp90 inhibitors has been approved yet because of their limitations in physico-chemical properties and/or safety profiles. However, recent reports have indicated that more than 10 new agents, 2nd generation of Hsp90 inhibitors with different chemotypes from GA and RD, have entered clinical trials and some of them showed clinical efficacy. In this review article, we describe the discoveries of major Hsp90 client proteins in the cancer field by RD derivatives, the history of KW-2478 discovery and development by Kyowa Hakko Kirin, and update the current status of new Hsp90 inhibitors in clinical trials.
    Current pharmaceutical design 08/2012; · 4.41 Impact Factor
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    ABSTRACT: The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.
    Blood Cancer Journal 07/2012; 2(7):e79. · 1.40 Impact Factor
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    ABSTRACT: Heat shock protein 90 (Hsp90) is a promising target for anti-tumor therapy. We previously reported the anti-tumor activity of a novel Hsp90 inhibitor, KW-2478, in multiple myeloma (MM) as a single agent. In this study, we examined the combinational effect of KW-2478 and bortezomib, a proteasome inhibitor, in vitro and in vivo. In vitro, KW-2478 enhanced bortezomib-induced cell growth inhibition, both in MM cell lines and primary patient MM cells. The combination of KW-2478 and bortezomib also induced caspase activation in MM cell lines. Interestingly, the combination synergistically enhanced the expression of Hsp70B, a homolog of Hsp70, in human MM cells and peripheral blood mononuclear cells, indicating Hsp70B could be a surrogate biomarker for the combination of Hsp90 and proteasome inhibitors. In vivo, the combination of KW-2478 with bortezomib showed synergistic anti-tumor activity without significant body weight loss in a subcutaneously inoculated human myeloma model. Furthermore, the combination also showed synergistic reduction of tumor burden in bone marrow in an orthotopic myeloma model. Our results strongly suggest that combination of KW-2478 with bortezomib could exhibit enhanced anti-tumor activity against human myeloma.
    Blood Cancer Journal 04/2012; 2(4):e68. · 1.40 Impact Factor
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    ABSTRACT: Activating mutations of KIT play an important role in the pathophysiology of several human malignancies, including acute myeloid leukemia. Activated KIT kinase is therefore a promising molecular target for the treatment of many malignancies harboring KIT activation. Here we examined the potency of a novel KIT inhibitor KI-328 against different types of mutant KIT kinases recurrently identified in AML. KI-328 shows selective potency against KIT kinase for the in vitro kinase assay, and inhibits the growth of wild-type (Wt)- and mutant-KIT-expressing cells, while it has little potency against D816V-KIT. Comparable analysis of several potent KIT inhibitors regarding growth inhibitory effects on a variety of mutant-KIT-expressing cells revealed that multi-kinase inhibitors have the same potency against D816V-KIT as other mutant KITs; however, the predominant potency against D816V-KIT was observed in heat shock protein 90 (HSP90) inhibitors. Furthermore, HSP90 inhibitors suppress the growth of D816V-KIT-expressing cells at the concentration at which the growth of other mutant-KIT-expressing cells is not affected. These results collectively indicated that potent KIT inhibitors have different potency against the type of mutant KIT kinases. Therefore, KIT inhibitors are required to validate potency against several types of mutant KIT kinases for the clinical development.
    International journal of hematology 10/2010; 92(4):624-33. · 1.17 Impact Factor
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    ABSTRACT: Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2010; 24(8):1506-12. · 10.16 Impact Factor
  • Taisuke Nakata, Hiroyuki Ishida, Yukimasa Shiotsu
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    ABSTRACT: More than 60 percents of breast cancers occur in post menopausal women and most of their initial stages are hormone dependent. For the treatment of estrogen dependent breast tumors, mainly two treatment tools are available, one is selective estrogen receptor modulator (SERM), and the other is aromatase inhibitor (AI). Although these drugs are clinically valuable, the existence of resistant tumors againt these two treatments is one of the most serious matters. The latest studies clarify that to inhibit the local formation of estrogen is more important than to decrease the estrogen dose in plasma. Steroid sulfatase (STS) is mainly expressed in local breast carcinoma tissues and is one of the most promising targets to inhibit the local formation of estrogens.
    Nippon rinsho. Japanese journal of clinical medicine 06/2010; 68(6):1073-8.
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    ABSTRACT: The heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client proteins in multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown antitumor activities both in vitro and in vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated. We evaluated the antitumor activities of KW-2478, a nonansamycin Hsp90 inhibitor, in MM cells with various chromosomal translocations of immunoglobulin heavy chain (IgH) loci both in vitro and in vivo. Our studies revealed that exposure of KW-2478 to MM cells resulted in growth inhibition and apoptosis, which were associated with degradation of well-known client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1), and FGFR3 was shown to be a new client protein of Hsp90 chaperon complex. In addition, KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. In NCI-H929 s.c. inoculated model, KW-2478 showed a significant suppression of tumor growth and induced the degradation of client proteins in tumors. Furthermore, in a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein, KW-2478 showed a significant reduction of both serum M protein and MM tumor burden in the bone marrow. These results suggest that targeting such diverse pathways by KW-2478 could be a promising strategy for the treatment of MM with various cytogenetic abnormalities.
    Clinical Cancer Research 05/2010; 16(10):2792-802. · 7.84 Impact Factor
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    ABSTRACT: Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2009; 24(1):33-43. · 10.16 Impact Factor
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    ABSTRACT: KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
    Blood 07/2009; 114(8):1607-17. · 9.06 Impact Factor
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    ABSTRACT: In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17beta-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor beta, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.
    The Journal of steroid biochemistry and molecular biology 01/2009; 113(3-5):195-201. · 2.66 Impact Factor
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    ABSTRACT: Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but FLT3 targeted therapy has produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multitargeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting.
    Blood 12/2008; 113(17):3938-46. · 9.06 Impact Factor
  • Folia Pharmacologica Japonica 11/2008; 132(4):217-20.
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    ABSTRACT: 5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.
    Bioorganic & medicinal chemistry letters 10/2008; 18(20):5472-7. · 2.65 Impact Factor
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    ABSTRACT: We screened a series of 17beta-(N-alkylcarbamoyl)-estra-1,3,5(10)trine-3-O-sulfamate derivatives, and describe here a potent and selective steroid sulfatase (STS) inhibitor with antitumor effects in breast cancer models in vitro and in vivo. In biochemical assays using crude enzymes isolated from recombinant Chinese hamster ovary cells expressing human arylsulfatses (ARSs), one of the best compounds, KW-2581, inhibited STS activity with an IC(50) of 4.0 nM, while > 1000-fold higher concentrations were required to inhibit the other ARSs. The failure to stimulate the growth of MCF-7 human breast cancer cells as well as in uteri in ovariectomized rats indicated the lack of estrogenicity of this compound. In MCF-7 cells transfected with the STS gene, termed MCS-2 cells, KW-2581 inhibited the growth of cells stimulated by estrone sulfate (E1S) but also 5-androstene-3beta, 17beta-diol 3-sulfate (ADIOLS) and dehydroepiandrostenedione 3-sulfate. We found that oral administration of KW-2581 inhibited both E1S- and ADIOLS-stimulated growth of MCS-2 cells in a mouse hollow fiber model. In a nitrosomethylurea-induced rat mammary tumor model, KW-2581 induced regression of E1S-stimulated tumor growth as effectively as tamoxifen or another STS inhibitor, 667 Coumate. Dose-response studies in the same rat model demonstrated that more than 90% inhibition of STS activity in tumors was necessary to induce tumor shrinkage. STS activity in tumors has well correlated with that in leukocytes, suggesting that STS activity in leukocytes could be used as an easily detectable pharmacodynamic marker. These findings demonstrate that KW-2581 is a candidate for development as a therapeutic agent for the treatment of hormone receptors-positive breast cancer.
    Breast Cancer Research and Treatment 12/2007; 106(2):215-27. · 4.47 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3-expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models. FI-700 showed a potent IC(50) value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)-driven growth of Wt-FLT3-expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G(1) arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C. FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.
    Clinical Cancer Research 09/2007; 13(15 Pt 1):4575-82. · 7.84 Impact Factor
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    ABSTRACT: Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, and thus inhibit the signal transduction pathway. In addition, direct binding of radicicol to the N-terminal ATP/ADP binding site of Hsp90 was shown, and thus radicicol has been recognized as a structurally unique antibiotic that binds and inhibits the molecular chaperone Hsp90. Although radicicol itself has little or no activity in animals because of instability in animals, its oxime derivatives showed potent antitumor activities against human tumor xenograft models. Hsp90 client proteins were depleted and apoptosis was induced in the tumor specimen treated with radicicol oxime derivatives. Taken together, these results suggest that the antitumor activity of radicicol oxime derivatives is mediated by binding to Hsp90 and destabilization of Hsp90 client proteins in the tumor. Among Hsp90 clients, we focused on ErbB2 and Bcr-Abl as examples of important targets of Hsp90 inhibitors. Radicicol oxime showed potent antitumor activity against ER negative/ErbB2 overexpressing breast cancer and Bcr-Abl expressing CML. Putative mechanisms of action and future directions of radicicol oxime against these kinds of tumor are discussed.
    Current Cancer Drug Targets 11/2003; 3(5):359-69. · 4.00 Impact Factor
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    ABSTRACT: Steroid sulfatase (STS) hydrolyzes inactive estrone sulfate (E1-S) to estrone (E1), while estrogen sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates estrogens to estrogen sulfates. They are considered to play important roles in the regulation of local estrogenic actions in various human tissues, however, their biological significance remains largely unknown. Therefore, we examined the expression of STS and EST in non-pathologic human tissues and breast carcinomas. STS expression was very weak except for the placenta, while EST expression was markedly detected in various tissues examined. In breast carcinoma tissues, STS and EST immunoreactivity was detected in carcinoma cells in 74 and 44% of cases, respectively, and was significantly associated with their mRNA levels and enzymatic activities. STS immunoreactivity was significantly correlated with the tumor size, and an increased risk of recurrence. EST immunoreactivity was inversely correlated with the tumor size or lymph node status. Moreover, EST immunoreactivity was significantly associated with a decreased risk of recurrence or improved prognosis. Our results suggest that EST is involved in protecting various peripheral tissues from excessive estrogenic effects. In the breast carcinoma, STS and EST are suggested to play important roles in the regulation of in situ estrogen production in the breast carcinomas.
    The Journal of Steroid Biochemistry and Molecular Biology 10/2003; 86(3-5):449-54. · 3.98 Impact Factor
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    ABSTRACT: More than two-thirds of breast cancers occur in post-menopausal women, and depend on the estrogens for their proliferation and survival. For the treatment of estrogen-dependent breast cancers, two major treatment options are now available. One is selective estrogen receptor modulator (SERM) such as Tamoxifen and another is aromatase inhibitor such as Anastrozole, Letrozole and Exemestane, which reduce local in situ formation of estrogens. Although these therapies are clinically active for advanced and early breast cancers, de novo and/or acquired resistance to SERM and/or aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of estrogens in the breast tumors is more important than circulating estrogen in plasma for the growth and survival of estrogen-dependent breast cancer in post-menopausal women. The rationale for the importance of local formation of estrogens is based on the following evidences. Estradiol (E2) levels in breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in breast tumors of post-menopausal women are 10-40 times higher than serum level. Biosynthesis of estrogens in breast tumors tissues occurs via two major different routes, one is aromatase pathway and another is steroid-sulfatase (STS) pathway. Whereas many studies has been reported about aromatase inhibitor and its clinical trial results in breast cancer patients, limited information are available regarding to other estrogen regulating enzymes including STS, its role in breast tumors and STS inhibitors. STS is the enzyme that hydrolyses estrone 3-sulfate (E1S) and dehydroepiandrosterone-sulfate (DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of estrogen-dependent breast tumors. It has been well known that E1S level are much higher than E2 level both in plasma and tumor of post-menopausal patients. Recent reports show that more than 80% of breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in breast cancer. Taking these findings into consideration, local formation of estrogens could be partially synthesized from large amount of E1S by STS, which exist in breast cancer. On the other hand, aromatase localizes in stroma and adipocyte surrounding breast cancer. Furthermore, since estrogen formation from E1S and DHEA-S (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of estrogen-dependent tumor post-SERM and/or aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal breast cancer patients is reviewed as well as STS inhibitor.
    The Journal of Steroid Biochemistry and Molecular Biology 10/2003; 86(3-5):455-60. · 3.98 Impact Factor
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    ABSTRACT: Radicicol (1), a macrocyclic antifungal antibiotic, is the lead compound of a novel class of heat shock protein 90 (Hsp90) inhibitors that result in the inhibition or degradation of Hsp90-associated proteins, such as v-src and Raf-1 kinases. New O-carbamoylmethyloxime derivatives of 1 were synthesized and evaluated for their in vitro antiproliferative activities against v-src- and K-ras-transformed cells and for their inhibitory activity against v-src tyrosine kinase. O-(Piperidinocarbonyl)methyloxime 9b, one of the most potent of these derivatives, exhibited more potent antiproliferative activity than 1 and its hydroxime KF25706 (2) and had an IC(50) of 25 nM for the inhibition of v-src kinase activity. Compound 9b was also found to decrease the Raf-1 protein level of KNRK5.2 cells. Furthermore, compound 9b exhibited significant antitumor activity when tested against MX-1 and A431 xenografts in nude mice.
    Journal of Medicinal Chemistry 07/2003; 46(12):2534-41. · 5.61 Impact Factor
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    ABSTRACT: Estrogens play a key role in various target tissues. Enzymes involved in the biosynthesis and metabolism of these sex steroids also regulate estrogenic actions in these tissues. Estrone sulfate (E1S) is a major circulating plasma estrogen that is converted into the biologically active estrogen, estrone (E1), by steroid sulfatase (STS). E1 is also sulfated and reverted into E1S by estrogen sulfotransferase (EST). These two enzymes have recently been shown to play important roles in the in situ estrogen actions of various sex steroid-dependent human tumors. However, the distribution of STS and EST in normal adult and fetal human tissues remains largely unknown. Therefore, in this study, in addition to examining the tissue distribution of both STS and EST mRNA in human adult and fetal tissues using RT followed by quantitative PCR, we studied the activity of these enzymes using (3)H-labeled E1/E1S as substrates in the homogenates of various human adult tissues. We also examined the localization of STS and EST protein in human adult and fetal tissues using immunohistochemistry, and that of EST mRNA in the adult kidney using laser dissection microscopy and PCR. STS mRNA, enzyme activity, and immunoreactivity were either absent or detected at very low levels in all adult and fetal tissues examined in this study. EST mRNA expression, however, was detected in all of the tissues examined, except for adult spleen and pancreas. EST enzyme activities were consistent with those of mRNA expression in the great majority of the tissues examined. Marked EST immunoreactivity was detected in hepatocytes, adrenal gland (adult, zona fasciculate to the reticularis; fetus, fetal zone), and epithelial cells of the gastrointestinal tract, smooth muscle cells of the tunica media in aorta, Leydig cells of the testis, and syncytiotrophoblast of the placenta. Patterns of EST immunolocalization were similar between adult and fetal human tissues, but EST immunoreactivity was detected in the urinary tubules of adult kidney, whereas in the fetal kidney, it was localized in the interstitial cells surrounding the urinary tubules. In the adult kidney, the presence of EST mRNA was also confirmed in the cells of urinary tubules using laser dissection microscopy and RT-PCR. Although the number of human tissues available for examination in this study was limited, our results suggest that between the enzymes involved in estrogen activation or inactivation, EST and not STS is the more widely expressed enzyme in various peripheral tissues in humans. We speculate that EST may play an important role in protecting peripheral tissues from possible excessive estrogenic effects.
    Journal of Clinical Endocrinology &amp Metabolism 01/2003; 87(12):5760-8. · 6.43 Impact Factor

Publication Stats

546 Citations
133.97 Total Impact Points

Institutions

  • 2000–2012
    • Kyowa Hakko Kirin
      Edo, Tōkyō, Japan
  • 1999–2010
    • KYOWA HAKKO BIO Co., Ltd.
      Edo, Tōkyō, Japan
  • 2007
    • Nagoya University
      Nagoya, Aichi, Japan