Biomedical subjects

M Suganuma

Publications and source records attributed to M Suganuma.

At least 19 recordsLinked to original sources

PubMed2004

Carcinogenic potential of tobacco tar-resistant Staphylococcus aureus in buccal cavity.

PURPOSE: The effects of cigarette smoking on the association between inflammation and cancer were studied, since some bacteria induce the production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine and endogenous tumor promoter, in cells. METHODS: Bacteria from a gargled solution from the buccal cavity of 20 individuals were cultured in the presence of 4 mg/ml cigarette-smoke condensates. Although cigarette-smoke condensates inhibited growth of Staphylococcus aureus strongly and that of Staphylococcus warneri weakly, tobacco tar-resistant S. aureus and S. warneri were obtained. RESULTS: One tobacco tar-resistant S. aureus strain (Sa-TA10) induced expression of the TNF-alpha gene in both Bhas 42 cells (v-Ha-ras transfected BALB/3T3 cells) and human lung cancer cell line H226B, while one tobacco tar-resistant S. warneri (Sw-TA75) did not induce it significantly. Moreover, Sa-TA10 induced formation of transformed foci and soft-agar colony in Bhas 42 cells in cooperation with the v-Ha-ras gene. The results suggested that Sa-TA10 has carcinogenic potential, whereas Sw-TA75 does not. CONCLUSION: These data suggest that tobacco tar-resistant S. aureus, with carcinogenic potential, is present in the buccal cavity of some individuals, and that cigarette smoking simultaneously inhibits growth of most of the bacteria and selects carcinogenic bacteria.

3T3 Cells↗

PubMed2003

Isolation and synthesis of TNF-alpha release inhibitors from Fijian kawa (Piper methysticum).

Two unique evidence that cancer incidence rates in Fiji were unusually low, compared with those of another Pacific islands and that green tea beverage is an acknowledged cancer preventive in Japan, allowed us to study a local beverage in Fiji, kawa (kava kava) or yangona (Piper methysticum) belonging to Piperaceae. We isolated five known kawapyrones (kavapyrones) (1-5) and a new additional kawapyrone, 7,8-epoxyyangonin (6), from kawa MeOH extract and subjected them to TNF-alpha (tumor necrosis factor-alpha) release assay from BALB/3T3 cells treated with okadaic acid, a tumor promoter. 5,6-Dehydrokawain (desmethoxyyangonin)(1) and yangonin (4) significantly inhibited TNF-alpha release with IC50 values of 17 microM and 40 microM; a potency as great as (-)-epigallocatechin gallate (EGCG) isolated from green tea extract. Among the experiments with 1-5, dihydrokawain (2) was unique in showing the strongest inhibitory activity against TNF-alpha release in mice, but the weakest activity in the cells. We synthesized 5,6-dehydrokawain (1) and yangonin (4) via three steps from the dianion of ethyl acetoacetate achieving a good yield and determined their conformations by high resolution NMR and x-ray crystallographic analysis.

Animals↗

PubMed2002

Discrete roles of cytokines, TNF-alpha, IL-1, IL-6 in tumor promotion and cell transformation.

Based on our previous results, which pointed to tumor necrosis factor-alpha (TNF-alpha) as the essential cytokine in tumor promotion in mouse skin, we present here three principal findings related to the specific roles of TNF-alpha, interleukin-1 (IL-1) and IL-6 in tumor promotion (using TNF-alpha- and IL-6-deficient mice) and in BALB/3T3 cell transformation: i) The previously reported residual tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in TNF-/- mice was confirmed by experiments with TNF+/+ and TNF-/- 129/Svj mice of the same strain, using two-stage carcinogenesis experiments. TPA produced tumors in 100% of TNF+/+ and 78% of TNF-/- mice at 20 weeks, and the average number of tumors per mouse was 11.1 in the former group and 2.1 in the latter. Judging from the expression of various inflammatory cytokine genes in TNF+/+ and TNF-/- mice, the residual tumor promoting activity of TPA in TNF-/- mice may be dependent on expression of IL-1alpha and IL-1beta genes. ii) Tumor promotion by TPA and okadaic acid in IL-6+/+ and IL-6-/- C57/BL6 mice was studied, with TPA producing tumors in 57.1% of IL-6+/+ and 40.0% of IL-6-/- mice at 20 weeks, and okadaic acid in 40.0% of IL-6+/+ and 53.3% of IL-6-/- mice. Thus, there was no significant difference between TPA or okadaic acid tumor promotion in either group. In addition, expression of IL-6 gene in skin of both types of mice suggested that IL-6 is not the essential cytokine in tumor promotion, since it can be replaced by other cytokines. iii) In transformed clones of BALB/3T3 cells induced by TNF-alpha alone, IL-1alpha gene expression was induced after transformation by TNF-alpha had occurred, which did not occur in parental cells. Expression patterns of TNF-alpha, IL-1beta, IL-6 and IL-10, along with TGF-beta, were similar in both parental and transformed cells. Considering all these results, we conclude that various cytokines have discrete roles in tumor promotion and cell transformation.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

Cancer prevention with green tea and monitoring by a new biomarker, hnRNP B1.

The study of green tea polyphenols as a cancer preventative is approaching a new era, with significant results accumulating rapidly. This paper briefly reviews four topics related to mechanisms of action of tea polyphenols: (I) identification of the genes commonly affected by EGCG, as demonstrated by Clontech's Atlas cDNA Expression Array; (II) the significance of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) as a new biomarker for early detection of lung cancer, and inhibition of its expression by EGCG; (III) the synergistic or additive effects of EGCG with the cancer preventive agents, sulindac and tamoxifen, on induction of apoptosis in PC-9 cells and on inhibition of intestinal tumor development in multiple intestinal neoplasia (Min) mice; (IV) the results of a 10 year prospective cohort study demonstrating the effectiveness of daily consumption of green tea in preventing cancer, and a prototype study for developing green tea beverage as cancer preventive.

Animals↗

PubMed2001

Helicobacter pylori membrane protein 1: a new carcinogenic factor of Helicobacter pylori.

Considering a suspected link between Helicobacter pylori infection and human stomach cancer, a new H. pylori gene for membrane protein 1 (HP-MP1) was recently cloned. Because HP-MP1 induces release of inflammatory cytokines and tumor necrosis factor-alpha acts as both initiator and tumor promoter, we studied the possible involvement of HP-MP1 in carcinogenesis of H. pylori. Two cell lines, BALB/3T3 cells as control and v-Ha-ras-transfected BALB/3T3 cells (Bhas 42 cells) as putative initiated cells, were each transfected with HP-MP1, urease B genes, or vector alone. All of the Bhas/mpl clones showed strong expression of tumor necrosis factor-alpha gene and produced tumors in 100% of nude mice. Two Bhas/ure clones showed weak tumorigenicity; the other Bhas and BALB clones showed none. Results indicate strong carcinogenic activity of HP-MP1 in cooperation with viral Ras protein and weak activity of urease B.

3T3 Cells↗

PubMed2001

Combination cancer chemoprevention with green tea extract and sulindac shown in intestinal tumor formation in Min mice.

Green tea is the most effective beverage for cancer prevention in humans. Looking at the concept of combination cancer chemoprevention, we previously reported the synergistic effects of (-)-epigallocatechin gallate (EGCG) with sulindac, and the additive effects of EGCG with tamoxifen, on cancer-preventive activity in human lung cancer cell line PC-9. This paper reports confirmation of the synergistic effects of EGCG with sulindac on the inhibition of intestinal tumors in multiple intestinal neoplasia (Min) mice. Treatment with both green tea extract and sulindac significantly reduced the number of tumors from 72.3 +/- 28.3 to 32.0 +/- 18.7 tumors per mouse, a decrease of 44.3%, whereas treatment with green tea extract alone or with sulindac alone reduced it to 56.7 +/- 3.5 and 49.0 +/- 12.7, respectively. The results also indicated that green tea extract inhibited tumor growth in Min mice almost as potently as sulindac itself did. The three treated groups did not show any adenocarcinomas, whereas 10.8% of the control group did. Since cancer-preventive agents like sulindac and tamoxifen are associated with adverse effects, we discuss the possibility of non-toxic, combination cancer chemoprevention with green tea, looking at the goal of truly effective cancer prevention.

Adenocarcinoma↗

PubMed2001

Spontaneous necrosis of gallbladder carcinoma in patient with pancreaticobiliary maljunction.

While gallbladder carcinoma is occasionally associated with pancreaticobiliary maljunction, spontaneous necrosis of carcinoma is extremely rare. We herein present a case of spontaneous necrosis of gallbladder carcinoma associated with direct invasion of viable cancer cell nests to the muscularis propria and subserosal layer located beneath the primary nodules. A 65-year-old Japanese man was admitted to a local hospital, complaining of repeated discomfort in the right hypochondrium. Ultrasonography and computed tomography scanning revealed cholecystitis associated with gallstones. Cholecystectomy was performed, and operative cholangiography demonstrated pancreaticobiliary maljunction. The resected gallbladder showed multiple mixed stones filled with necrotic debris and bile sludge. Scrutiny of the mucosal surface revealed multiple small necrotic nodules in the fundus, which were histologically confirmed to be necrotic remnants of a cancerous glandular structure. Small nests of papillary adenocarcinoma were found beneath the nodules in the muscularis propria and in the venous structure located in the connective tissues next to the divided margin of the gallbladder bed. Resection of S4a and S5 of the liver and resection of the extrahepatic bile duct was then performed to remove the remaining cancerous tissues and/or micrometastasis in the liver and bile duct. The biliary tree was reconstructed with a hepaticoduodenostomy. No cancer nests or any precancerous lesions were found in the additionally resected specimens. This case indicates a unique morphological feature of gallbladder carcinoma associated with pancreaticobiliary maljunction, which provides some insight into the pathogenesis of spontaneous necrosis of gallbladder carcinoma.

Adenocarcinoma, Papillary↗

PubMed2001

Psoas abscess and cellulitis of the right gluteal region resulting from carcinoma of the cecum.

Although retroperitoneal or psoas abscess is an unusual clinical problem, the insidious and occult characteristics of this abscess sometimes cause diagnostic delays, resulting in considerably high morbidity and mortality. In particular, psoas abscess caused by perforated colon carcinoma is uncommon. We report a case of psoas abscess caused by a carcinoma of the cecum. A 72-year-old Japanese woman was admitted to our hospital, with pain in the right groin and buttock. The pain had appeared 6 months before admission, and the symptoms had then been relieved by oral antibiotics. On March 25, 1999, inflammatory signs in the right buttock indicated localized cellulitis, and incision and drainage was performed at a local hospital. The patient was referred to our hospital on the same day. On admission to our hospital, computed tomography (CT) scan revealed a thick right-sided colonic wall and enlargement of the right ileopsoas muscle. Barium enema and colonofiberscopy revealed an ulcerated tumor occupying the entire circumference of the cecum. A retroperitoneal abscess and fistula had been formed by the retroperitoneal perforation of cecum carcinoma: surgical resection was performed after remission of the local inflammatory signs. Operative findings indicated that the cancerous lesion and its surrounding tissues were firmly attached to the right iliopsoas and major psoas muscle, and en-bloc resection, including adjacent muscular tissue, was performed. The fact that carcinoma of the colon could be a cause of psoas abscess and cellulitis in the gluteal region should be considered when an unexplained psoas abscess is diagnosed.

Adenocarcinoma↗

PubMed2001

A new function of green tea: prevention of lifestyle-related diseases.

In the normal human life span, there occur lifestyle-related diseases that may be preventable with nontoxic agents. This paper deals with the preventive activity of green tea in some lifestyle-related diseases. Green tea is one of the most practical cancer preventives, as we have shown in various in vitro and in vivo experiments, along with epidemiological studies. Among various biological effects of green tea, we have focused on its inhibitory effect on TNF-alpha gene expression mediated through inhibition of NF-kappaB and AP-1 activation. Based on our recent results with TNF-alpha-deficient mice, TNF-alpha is an endogenous tumor promoter. TNF-alpha is also known to be a central mediator in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. We therefore hypothesized that green tea might be a preventive agent for chronic inflammatory diseases. To test this hypothesis, TNF-alpha transgenic mice, which overexpress TNF-alpha only in the lungs, were examined. The TNF-alpha transgenic mouse is an animal model of human idiopathic pulmonary fibrosis which also frequently develops lung cancer. Expressions of TNF-alpha and IL-6 were inhibited in the lungs of these mice after treatment with green tea in drinking water for 4 months. In addition, judging from the results of a prospective cohort study in Saitama Prefecture, Japan, green tea helps to prevent cardiovascular disease. In this study, a decreased relative risk of death from cardiovascular disease was found for people consuming over 10 cups of green tea a day, and green tea also had life-prolonging effects on cumulative survival. These data suggest that green tea has preventive effects on both chronic inflammatory diseases and lifestyle-related diseases (including cardiovascular disease and cancer), resulting in prolongation of life span.

Animals↗

PubMed2001

New TNF-alpha releasing inhibitors, geraniin and corilagin, in leaves of Acer nikoense, Megusurino-ki.

The success of green tea as a cancer preventive is based on evidence that green tea contains tannins and antioxidants, does not show toxicity in humans and has long traditional use in Asia. In the light of this, herbal medicines are now also attracting attention as potential sources of cancer preventive agents. Using the inhibition of TNF-alpha release assay, we studied Acer nikoense (Megusurino-ki in Japanese), one of the herbal medicines. The inhibitory activity of TNF-alpha release was found in the leaf extract rather than the bark extract, and the main active constituents were identified as geraniin and corilagin, which are present in another Japanese traditional herb, Geranium thunbergii (Genno-shoko). The IC50 values of TNF-alpha release inhibition were 43 microM for geraniin and 76 microM for corilagin, whereas that for (-)-epigallocatechin gallate (EGCG) was 26 microM. Treatment with geraniin prior to application of okadaic acid, a tumor promoter on mouse skin initiated with 7,12-dimethylbenz(a)anthracene, reduced the percentage of tumor-bearing mice from 80.0 to 40.0% and the average numbers of tumor per mouse from 3.8 to 1.1 in week 20. Thus, geraniin has slightly weaker inhibitory activity than EGCG. Since geraniin and corilagin have been well investigated as representative tannins, we discuss here the new possibility of classical herbal medicine in the development of preventive agents for cancer and other life-style related diseases.

3T3 Cells↗

PubMed2001

Modulation of gene expression by (-)-epigallocatechin gallate in PC-9 cells using a cDNA expression array.

Green tea is the most effective cancer preventive beverage. In the light of this, the mechanisms of action of tea polyphenols were investigated on the molecular levels. We present here the effects of (-)-epigallocatechin gallate (EGCG) on expression of 588 genes in human lung cancer cell line PC-9 cells, using a human cancer cDNA expression array. The levels of gene expression in non-treated control cells, and cells treated with EGCG alone, with the tumor promoter okadaic acid alone, and with EGCG plus okadaic acid, were studied, and their expression levels were classified into down-regulation (under 0.5 fold) and up-regulation (over 2.0 fold) by comparing with the levels of control. Non-treated PC-9 cells expressed 163 genes out of 588, and EGCG-treated cells induced down-regulated expression of 12 genes and up-regulated expression of 4 other genes. From a comparison of gene expression in the cells treated with EGCG and in cells treated with EGCG plus okadaic acid, we found the following genes commonly affected by EGCG: down-regulation of four genes, NF-kappaB inducing kinase (NIK), death-associated protein kinase 1 (DAPK 1), rhoB and tyrosine-protein kinase (SKY); up-regulation of one gene, retinoic acid receptor alpha1. Among them, we think down-regulation of NIK gene expression is significant for cancer prevention, based on evidence that inhibition of NF-kappaB activation is a result of inhibition of NIK/IKK signalling complex.

Antimutagenic Agents↗

PubMed2001

[Three-dimensional curve tracing].

The time required in judging if two probes are on the same curve increased monotonically with the separation of the probes along that curve. This process is called "curve tracing" (Jolicoeur, Ullman & Mackay, 1986). In this study we examined whether curve tracing would occur on a three-dimensionally presented curve with depth variation. By comparing the performance on depth varying and no depth varying stimuli, we examined the properties of three-dimensional curve tracing. The mean RT on three-dimensional stimuli increased monotonically as the distance between two probes increased, which indicates that curve tracing also occurs on three-dimensional stimuli. The mean RT on three-dimensional stimuli was longer than that on two-dimensional stimuli. Our results suggest that three-dimensional structure of the stimuli caused additional costs on curve tracing.

Adult↗

PubMed2000

Evidence that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-kappaB.

The transcription factor NF-kappaB is a positive transcription factor for a number of genes and has been recognized as an anti-apoptotic regulator. However, the mechanism by which NF-kappaB blocks apoptosis is still controversial. Here, we demonstrate the evidence that NF-kappaB could attenuate the TNF-alpha-induced apoptosis without de novo protein synthesis using human pancreatic cancer cell lines, MIA PaCa-2 and Capan-2. The TNF-alpha-induced apoptosis was blocked by IL-1beta, a potent inducer of NF-kappaB activation. This inhibitory effect of IL-1beta was evident when cells were treated with protein synthesis inhibitors such as cycloheximide (CHX). Moreover, NF-kappaB decoy oligonucleotides could not block the anti-apoptotic effect of IL-1beta at doses sufficient to block the NF-kappaB-dependent transcription induced by IL-1beta. To confirm the role of NF-kappaB in blocking apoptosis, we generated stable cell lines expressing IkappaBdeltaN, a highly stable form of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB. In these stable transfectants, the antiapoptotic effect of IL-1beta was totally abolished, indicating that the anti-apoptotic action of IL-1beta could be ascribed to the NF-kappaB action. These findings show that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-kappaB and support the possibility that NF-kappaB could exert its anti-apoptotic action through protein-protein interaction.

Apoptosis↗

PubMed2000

Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention.

The significance of drinking green tea in prevention of two of the main lifestyle-related diseases, cancer and cardiovascular disease, was demonstrated in terms of a prospective cohort study on a total of 8,552 general residents in Saitama Prefecture, Japan. On the basis of the follow-up study, we revealed decreased relative risk of cancer incidence for those consuming over 10 cups a day, compared with those consuming below 3 cups: 0.54 (95% confidence interval, 0.22-1.34) for men, 0.57 (0.34-0.98) for women, and 0.59 (0.35-0.98) for both sexes. Furthermore, a significant delay in cancer onset was associated with increased consumption of green tea. Next, decreased relative risk of death from cardiovascular disease was 0.58 (0.34-0.99) for men, 0.82 (0.49-1.38) for women, and 0.72 (0.60-1.04) for members of both sexes consuming over 10 cups a day. Finally, we evaluated the life-prolonging effects of drinking green tea on cumulative survival, using the life table.

Adult↗

PubMed2000

Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF-alpha expression.

Among various biochemical and biological activities of tea polyphenols, we believe inhibition of the expression and release of tumor necrosis factor-alpha (TNF-alpha) is crucial, since our study with TNF-alpha-deficient mice has revealed that TNF-alpha is an essential factor in tumor promotion. We found that EGCG dose-dependently inhibited AP-1 and NF-kappaB activation in BALB/3T3 cells treated with okadaic acid, resulting in inhibition of TNF-alpha gene expression. Furthermore, treatment with 0.1% green tea extract in drinking water reduced TNF-alpha gene expression as well as TNF-alpha protein level in the lung of TNF-alpha transgenic mice; and IL-1beta and IL-10 gene expression in the lung was also inhibited by treatment with green tea extract, indicating that green tea inhibits both TNF-alpha and the cytokines induced by TNF-alpha in organs. We recently found synergistic effects of EGCG and cancer preventive agents such as tamoxifen and sulindac, on cancer preventive activity. Taken together, the results show that green tea is efficacious as a non-toxic cancer preventive for humans.

3T3 Cells↗

PubMed2000

A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review.

The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters has revealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF-alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate tumor promotion and progression of initiated cells as well as premalignant cells. The first part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidence that pretreatment with agents such as tamoxifen, sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and the general population.

Animals↗

PubMed1999

Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation.

We devised two short peptides corresponding to amino acids 211-221 of human Cdc25C fused with a part of HIV1-TAT. These peptides inhibited hChk1 and Chk2/HuCds1 kinase activity in vitro and specifically abrogated the G2 checkpoint in vivo. These peptides sensitized p53-defective cancer cell lines to DNA-damaging agent to death without obvious cytotoxic effect on normal cells. Our results clearly indicate that the specific abrogation of the cell cycle G2 checkpoint is a feasible strategy for cancer therapy, and hChk1 and Chk2/HuCds1 are proper targets for that purpose.

Amino Acid Sequence↗

PubMed1999

Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice.

To examine the hypothesis that tumor necrosis factor (TNF) alpha is an essential cytokine in carcinogenesis, we conducted two-stage carcinogenesis experiments with an initiator, 7,12-dimethylbenz(a)anthracene (DMBA), plus either of two tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13-acetate (TPA), on the skin of TNF-alpha-deficient (TNF-/-) mice. TNF-/- mice treated with DMBA plus okadaic acid developed no tumors for up to 19 weeks, and at 20 weeks, the percentage of tumor-bearing TNF-/- mice was 10%, whereas the percentage of tumor-bearing TNF+/+ mice was 100%. In TNF-/- mice treated with DMBA plus TPA, tumor onset was delayed 4 weeks, and the time to development of small tumors in 100% of mice was 9 weeks later than that seen in TNF+/+ CD-1 mice. The average number of tumors in TPA-treated TNF-/- mice was 2.8, compared with 11.8 for TNF+/+ CD-1 mice. To understand the residual tumor-promoting activity in TNF-/- mice, we also investigated the possible significance of interleukin (IL) 1 as an additional cytokine in tumor promotion. A single application of TPA and okadaic acid increased IL-1alpha and IL-1beta gene expression in TNF-/- mice. All of our results demonstrate that TNF-alpha is the key cytokine for tumor promotion in mouse skin and, very possibly, for carcinogenesis in humans as well.

3T3 Cells↗