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ABSTRACT: The anti-diabetic effect of cytogenin was examined using streptozotocin-induced diabetes in mice. Cytogenin suppressed not only the increase of plasma glucose level but also the body weight reduction in diabetic mice. Histological examination of the pancreas taken from diabetic mice given cytogenin showed that cytogenin decreased the number of macrophages infiltrated into islet of pancreas. Further, cytogenin suppressed the nitric oxide generation by macrophages treated with lipopolysaccharide through decreasing of inducible nitric oxide synthase expression. Cytogenin suppressed interleukin-6 expression by macrophage treated with LPS, suggesting that the anti-diabetic activity of cytogenin might be partly attributed to the suppressive activity against nitric oxide generation.
The Journal of Antibiotics 04/2005; 58(3):202-5. · 1.65 Impact Factor
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ABSTRACT: Deficiency of Fas expression is one of mechanisms involved in the immune evasion by tumors. Several antitumor drugs, such as doxorubicin (DOX) increase Fas expression in tumor cells and sensitize the cells to Fas-mediated apoptosis in vitro. However, the significance of the Fas expression in vivo is still unclear. Therefore, we examined a role of Fas expression on antitumor effect of DOX using a syngeneic tumor model of Lewis lung carcinoma (3LL) cells in C57BL/6-gld mice that lack functional Fas ligand (FasL). In vitro, anti-Fas agonistic antibody, Jo2, did not decrease a viable cell number of 3LL cells in the absence of DOX, whereas it significantly reduced the cell viability in the presence of DOX. The treatment with DOX alone at the same dose did not induce cell death. Flowcytometric analysis of Fas expression revealed that 3LL cells expressed only a marginal amount of Fas, but the treatment of the cells with DOX increased the expression of Fas in the cell surface. When splenic T cells were prepared from 3LL-bearing C57BL/6 mice, the splenic T cells significantly killed DOX-pretreated 3LL cells more than untreated 3LL cells. In the syngeneic models, DOX inhibited growth of 3LL solid tumor both in wild-type C57BL/6 mice and in Fas-deficient C57BL/6-lpr mice, but it failed in C57BL/6-gld mice, suggesting that the interaction between host FasL and tumor Fas is involved in the antitumor effect of DOX. Furthermore, Fas expression was increased in the solid tumor by the treatment of DOX. These results suggest that the antitumor effect of DOX is partly exerted by the Fas expression and host immune defense.
International Immunopharmacology 03/2005; 5(2):281-8. · 2.38 Impact Factor
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ABSTRACT: ICM0301A (1), B (2) and their congeners (3 approximately 8) were isolated from a culture broth of Aspergillus sp. F-1491 as new angiogenesis inhibitors. Their structures were elucidated by spectroscopic analyses. ICM0301A and B have a substituted decalin skeleton containing two oxirane rings.
The Journal of Antibiotics 03/2004; 57(2):104-9. · 1.65 Impact Factor
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ABSTRACT: In the course of screening program for inhibitors of angiogenesis, novel substances designated as ICM0301A approximately H (1 approximately 8) were isolated from the culture broth of Aspergillus sp. F-1491. ICM0301s inhibited the growth of human umbilical vein endothelial cells (HUVECs) induced by basic fibroblast growth factor (bFGF) with IC50 values of 2.2 approximately 9.3 microg/ml. ICM0301A (1) showed significant anti-angiogenic activity at lower than 10 microg/ml in the angiogenesis model using rat aorta cultured in fibrin gel. ICM0301s showed very low cytotoxicity against various tumor cells. Furthermore, 1CM0301A did not show any toxic symptom in mice by intraperitoneal injection at 100 mg/kg.
The Journal of Antibiotics 03/2004; 57(2):97-103. · 1.65 Impact Factor
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ABSTRACT: Androgen receptor (AR) is a ligand-activated transcription factor that requires androgen binding to initiate a series of molecular events leading to specific gene activation. AR has been suggested to form an antiparallel homodimer based on the characteristics of high affinity interaction between the amino (N) and carboxyl (C) termini of it. Recently, it is suggested that AR N-to-C interaction is critical for the ability of this receptor to up-regulate the transcription of androgen-responsive genes, and may be a new target for treatment of prostate cancer (PCa). In this study, we investigated the effect of N-terminal (1-34) peptide of AR (ARN34) on androgen-dependent function in PCa cell. Ectopic expression of ARN34 suppressed both androgen-dependent AR N-to-C interaction and prostate specific antigen transcription. Ectopic expression of ARN34 also caused delaying translocation to the nucleus and the decreasing stability of the AR. Stable expression of ARN34 suppressed androgen-dependent cell growth of LNCaP cells. Moreover, transactivation and cell growth of the AR variant in LNCaP cells by the AR antagonist, hydroxyflutamide, were also inhibited by ARN34. Although treatment of LNCaP cells with androgen drove transition of cells from G1 to S-phase, the cells expressing ARN34 were inhibited to enter into S phase in the presence of androgen. This cell cycle arrest was attended by decrease in cyclin E levels and cyclin-dependent-kinase 2 activity, and increase in p27 levels. Our results demonstrated that disruption of AR N-to-C interaction caused by ARN34 leads to AR dysfunction and inhibition of AR-mediated prostate cancer cell growth. This approach is thus considered to provide a useful therapeutic opinion for blocking AR-mediated PCa growth.
Molecular and Cellular Endocrinology 03/2004; 214(1-2):175-87. · 4.19 Impact Factor
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ABSTRACT: Novel antibiotics named kigamicin A, B, C, D, and E were discovered from the culture broth of Amycolatopsis sp. ML630-mF1 by their selective killing activity against PANC-1 cells only under a nutrient starved condition. Under a condition of nutrient starvation, kigamicins A, B, C, and D inhibited PANC-1 cell survival at 100 times lower concentration than in normal culture. Kigamicins showed antimicrobial activity against Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA). Kigamicin D inhibited the growth of various mouse tumor cell lines at IC50 of about 1 microg/ml.
The Journal of Antibiotics 01/2004; 56(12):1004-11. · 1.65 Impact Factor
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ABSTRACT: Nephrotoxicity is known to be a major clinical side effect of aminoglycoside antibiotics. Aminoglycosides cause damage to proximal tubular cells in kidney, however the mechanism of toxicity is still unclear. In order to elucidate the mechanism of nephrotoxicity, we studied the effect of aminoglycoside antibiotics on glucose transport systems in vitro and in vivo. As a result, we found that the aminoglycosides significantly reduced Na(+)/glucose cotransporter (SGLT1)-dependent glucose transport and also down-regulated mRNA and protein levels of the SGLT1 in pig proximal tubular LLC-PK(1) cells. To obtain evidence about SGLT1 down-regulation in vivo, we studied the mRNA expression of SGLT1 using gentamicin C-treated murine kidney and found that gentamicin C down-regulated SGLT1 in vivo as well as in vitro. Furthermore, the gentamicin C-treated mice showed significant rise in urinary glucose excretion. These results indicate that one of the mechanisms of aminoglycoside nephrotoxicity is the down-regulation of SGLT1, which causes reduction in glucose reabsorption in kidney.
Biochemical and Biophysical Research Communications 10/2003; 308(4):866-71. · 2.48 Impact Factor
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The Journal of Antibiotics 09/2003; 56(8):725-6. · 1.65 Impact Factor
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ABSTRACT: Imbalances in the epithelial-stromal interactions are important in the pathogenesis of prostate cancer. However, we know little about androgenic regulation in the stroma of prostate cancer. We examined the cancer-stromal interaction paying attention to androgen responsiveness of stromal side. In co-culture, PC3 and LNCaP cells did not affect dihydrotestosterone (DHT)-dependent growth of prostate stromal cells (PrSCs), but DU145 cells significantly reduced it. Conditioned medium from DU145 cells (DU145-CM) also inhibited DHT-dependent PrSCs growth, androgen receptor (AR) expression, and prostate specific antigen transcription. Although the inhibitory effect of DU145-CM was not affected by neutralizing antibody against EGF, FGF-2, or TNF-alpha, pretreatment with testosterone-Sepharose partially reduced the inhibitory ability of DU145-CM. These results suggest that DU145 cells produce inhibitory factors for androgen responsiveness, including steroid-binding protein(s), and these may participate in crosstalk between DU145 cells and PrSCs as modulators of androgen.
Biochemical and Biophysical Research Communications 08/2003; 306(3):629-36. · 2.48 Impact Factor
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ABSTRACT: In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.78 microg/ml and showed weak cytotoxicity against bone marrow cells.
The Journal of Antibiotics 04/2003; 56(3):209-13. · 1.65 Impact Factor
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ABSTRACT: ICM0201 (1), a new inhibitor of murine osteoclastogenesis in culture was isolated from a fermentation broth of Cunninghamella sp. F-1490. The structure of ICM0201 was determined to be (3S,10aR)-3,4a-dihydroxy-2,3,4,4a-tetrahydro-2H-pyrano[3,2-b]benzo[e]morpholine-9-carboxylic acid by spectroscopic analyses and chemical studies. The structure of 1 is unique in that the tricycle ring system is composed of aminal and hemiacetal bonds.
The Journal of Antibiotics 04/2003; 56(3):214-8. · 1.65 Impact Factor
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ABSTRACT: Selective augmentation of natural killer (NK) cells can suppress tumor metastasis, but molecular targets for NK cell activation have not been identified. We report here that cytostatin (CTS), a novel specific inhibitor of protein phosphatase (PP) 2A, can inhibit B16 melanoma pulmonary metastasis by the expansion and activation of NK cells. CTS administration in vivo increased mRNA expression of Flt-3 ligand, one of NK-generating cytokines, in bone marrow cells. Phoslactomycin A and leustroducsin H, other specific inhibitors of PP2A, also augmented NK cell activity and inhibited lung metastasis, but a CTS analogue without inhibitory activity on PP2A and calyculin A, a dual inhibitor of PP1 and PP2A, did not. These results suggest that specific inhibition of PP2A can augment NK cells through upregulation of NK-generating cytokine and prophylaxis for pulmonary metastasis.
International Immunopharmacology 03/2003; 3(2):179-88. · 2.38 Impact Factor
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ABSTRACT: Hygrolidin family antibiotics showed selective cytotoxicity against both cyclin E- and cyclin A-overexpressing cells. Among them, hygrolidin was the most potent and inhibited growth of solid tumor-derived cell lines such as DLD-1 human colon cancer cells efficiently more than that of hematopoietic tumor cells and normal fibroblasts. FACS analysis revealed that hygrolidin increased cells in G1 and S phases in DLD-1 cells. While hygrolidin decreased amounts of cyclin-dependent kinase (cdk) 4, cyclin D, and cyclin B, it increased cyclin E and p21 levels. Hygrolidin-induced p21 bound to and inhibit cyclin A-cdk2 complex more strongly than cyclin E-cdk2 complex. Furthermore, hygrolidin was found to increase p21 mRNA in DLD-1 cells, but not in normal fibroblasts. Thus, hygrolidin inhibited tumor cell growth through induction of p21. In respect to p21 induction, inhibition of vacuolar-type (H+)-ATPase by hygrolidin was suggested to be involved.
Biochemical and Biophysical Research Communications 11/2002; 298(1):178-83. · 2.48 Impact Factor
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ABSTRACT: 15-Deoxyspergualin (DSG) strongly inhibited growth of mouse EL-4 lymphoma cells in vitro and in vivo. It significantly prolonged the survival days of EL-4-transplanted mice. In vitro study revealed that its antiproliferative effect appeared only after 2 days of treatment. At that time, protein synthesis was significantly inhibited rather than DNA and RNA syntheses. Furthermore, DSG induced apoptosis without arresting the cell cycle. p70 S6 kinase (p70S6K), a key molecule in protein synthesis, was inhibited by 2 days of treatment of DSG. Akt, an upstream kinase of p70S6K, was also deactivated by 2 days of treatment of DSG. Hsp90 is reported to bind to and stabilize Akt kinase and also to bind to DSG. Yet DSG did not inhibit the binding of Hsp90 to Akt kinase. PI3-kinase, an activator of Akt, was not affected by DSG treatment. However, when we looked into phospholipid synthesis, we found that DSG inhibited phosphatidylcholine (PC) synthesis strongly rather than phosphatidylinositol even by 1 day of treatment. Moreover, DSG failed to inhibit Akt kinase activation and PC synthesis in DSG-less sensitive human K562 leukemia cells. These results demonstrate that DSG inhibits tumor cell growth through the inhibition of protein synthesis and induction of apoptosis, which is caused by the down-regulation of Akt kinase and p70S6K. It is also indicated that the down-regulation of Akt kinase by DSG should not depend on PI3-kinase and Hsp90. There might be possible involvement of PC in Akt kinase activity.
Journal of Biological Chemistry 09/2002; 277(31):27765-71. · 4.77 Impact Factor
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The Journal of Antibiotics 07/2002; 55(6):605-6. · 1.65 Impact Factor
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ABSTRACT: Recent studies have shown that integrin αvβ3, a receptor for vitronectin, plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of αvβ3 inhibit angiogenic processes including endothelial cell adhesion and migration. On the other hand, most inhibitors of integrin αvβ3 are peptide antagonists that include the Arg-Gly-Asp (RGD) motif. We therefore reasoned that non-peptide inhibitors of endothelial cell adhesion to vitronectin might be useful for inhibition of tumor angiogenesis in vivo. We screened for low-molecular-weight natural products able to inhibit adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin, and pyrrothine group compounds including aureothricin, thioaurin and thiolutin were isolated from microbial culture broths. Of these compounds, thiolutin inhibited adhesion of HUVECs to vitronectin the most effectively (IC50, 0.83 μM). In vivo experiments showed that thiolutin significantly suppressed angiogenesis induced by tumor cells (S-180), a pathological form of neovascularization, in a mouse dorsal air sac assay system. To explore the mechanism of inhibition of HUVEC adhesion to vitronectin by thiolutin, we examined the effect of this agent on intracellular cell adhesion signaling. We found that the amount of paxillin in HUVECs was significantly reduced by thiolutin treatment, while those of other focal adhesion proteins including vinculin and focal adhesion kinase (FAK) were not. Metabolic labeling experiments showed that thiolutin enhanced degradation of paxillin in HUVECs. Protease inhibitors (MG115 and E64-D) decreased the rate of degradation of the paxillin induced by thiolutin and partially restored thiolutin-induced inhibition of HUVEC adhesion to vitronectin. Based on these findings, we concluded that thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces the paxillin level in HUVECs and suppresses tumor cell-induced angiogenesis in vivo. © 2001 Wiley-Liss, Inc.
International Journal of Cancer 07/2001; 93(3):307 - 316. · 5.44 Impact Factor
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ABSTRACT: Cyclin D1 is frequently overexpressed in human esophageal cancer. We examined the possible role of cyclin D1 overexpression on specific malignant properties of tumor cells using a series of eight human esophageal cancer cell lines that express different levels of cyclin D1. We did not find a simple correlation between levels of cyclin D1 expression and anchorage-independent growth, production of angiogenic factors, or tumorigenicity in nude mice, suggesting that other factors can influence these parameters. We did, however, obtain evidence that tumorigenicity appeared to require both the capacity for anchorage-independent growth and the production of angiogenic factors. To better assess the specific role of cyclin D1, we stably expressed an antisense cyclin D1 cDNA construct in the tumorigenic cell line TTn. This significantly decreased anchorage-independent growth and VEGF production and led to a loss of tumorigenicity in nude mice. Furthermore, these cells diplayed a marked increase in sensitivity to antitumor agents and to Fas antibody-induced apoptosis. Taken together, these findings suggest that the overexpression of cyclin D1 can confer esophageal cancer cells with enhanced malignancy through increases in anchorage-independent growth and VEGF production, and down-regulation of Fas expression, thus suggesting novel functions of the cyclin D1 protein in tumor progression.
Anticancer research 22(2A):639-47. · 1.73 Impact Factor
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ABSTRACT: Stromal cells play an important role in regulating epithelial malignancies through diffusible factors and adhesion. Modulation of the tumor-stromal cell interaction is an attractive target for new antitumor strategies. To screen for a modulator of the interaction, we have now developed a quantitative colorimetric assay for measurement of tumor cell growth in coculture with stromal cells using rhodanile blue dye. Rhodanile blue specifically stained cytokeratin-positive tumor cells in the coculture. When human prostate carcinoma cells LNCaP, PC-3 and DU-145 were cocultured with normal prostate stromal cells (PrSC) in a microplate, growth of the prostate cancer cells in the coculture was selectively measured by the rhodanile blue staining method. Using this system, we searched for a modulator of the tumor-stromal cell interaction among clinically used drugs and natural products. As a result, we found that 5-fluorouracil, bleomycin and phthoxazolin A inhibit prostate cancer cell growth more strongly in coculture with PrSC than that in monoculture. Without need to pre-label cells and transfect a marker gene, our new method is simple, rapid and thus useful for screening for modulators of the tumor-stromal cell interaction. Furthermore, our results suggest that low molecular weight compounds modulate the tumor-stromal cell interaction.
Anticancer research 24(3a):1561-8. · 1.73 Impact Factor
