The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Kiyoshi Kurokawa - One of the best experts on this subject based on the ideXlab platform.
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involvement of down regulation resistant protein kinase c in Teleocidin inhibition of cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin in human hepatoma cells
Cancer Letters, 1993Co-Authors: Yoshiyasu Kaneko, Ayumi Tsukamoto, Kiyoshi KurokawaAbstract:Abstract Teleocidin, a phorbol ester-type tumor promoter, inhibits cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin in PLC/PRF/5 hepatoma cells. These inhibitory effects of Teleocidin were observed even after a prolonged exposure of the hepatoma cells to this promoter, suggesting the presence of down-regulation-resistant protein kinase C in this hepatoma cell line. Column chromatography of cytosolic fractions showed three separate peaks of protein kinase C activity, two being down-regulation-sensitive while one was down-regulation-resistant. This down-regulation-resistant PKC is suggested to be responsible for the inhibitory effect of Teleocidin on cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin.
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thapsigargin an inhibitor of endoplasmic reticulum ca2 atpase enhances c fos expression but antagonizes vacuole formation of human hepatoma cells induced by Teleocidin
Biochimica et Biophysica Acta, 1993Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Teleocidin, a phorbol ester-type tumor promoter, enhanced actin redistribution, vacuole formation and c-fos expression of PLC/PRF/5 hepatoma cells. This tumor promoter also inhibited calcium mobilization induced by epidermal growth factor (EGF). Thapsigargin, a specific inhibitor of endoplasmic reticulum Ca2+-ATPase, elevated cytosolic calcium, enhanced c-fos expression and antagonized the vacuole formation induced by Teleocidin without interfering with actin redistribution and Lucifer yellow uptake. On the other hand, a calcium ionophore ionomycin elevated both cytosolic Ca2+ and c-fos mRNA but could not antagonize the vacuole formation induced by Teleocidin. From these results it was speculated that the Ca2+ leak from the endoplasmic reticulum rather than the elevation of cytosolic Ca2+ appeared to be responsible for the specific inhibition of vacuole formation by thapsigargin.
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thapsigargin an inhibitor of endoplasmic reticulum ca2 atpase antagonizes cytokeratin assembly of human hepatoma cells induced by Teleocidin
International Hepatology Communications, 1993Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Abstract Teleocidin, a phorbol ester-type of tumor promoter markedly enhanced cytokeratin assembly of PLC/PRF/5 hepatoma cells. Thapsigargin, a non-phorbol ester-type tumor promoter which specifically inhibited endoplasmic reticulum Ca 2+ -ATPase, elevated cytosolic calcium and antagonized the cytokeratin assembly induced by Teleocidin. A calcium ionophore ionomycin mimicked the effect of thapsigargin, suggesting that elevated cytosolic calcium appeared to be responsible for the antagonistic action of thapsigargin on the cytokeratin assembly.
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novobiocin modulates cytokeratin assembly and differentiation of human hepatoma cells induced by butyrate and Teleocidin
Cancer Letters, 1991Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Abstract A differentiation inducer butyrate and a tumor promoter Teleocidin had inhibitory effects on the proliferation of PLC/PRF/5 hepatoma. Both of these reagents stimulated the production of procollagen type III peptide, enhanced the cytokeratin assembly and altered the morphological appearance. Novobiocin, a topoisomerase II inhibitor, enhanced the cytokeratin assembly induced by butyrate but antagonized that induced by Teleocidin without changing the expression and the phosphorylation state of cytokeratin proteins. In addition, novobiocin acted synergistically with butyrate but not with Teleocidin in stimulating the procollagen production and the acetate uptake. These results suggest that butyrate and Teleocidin induce cell differentiation via distinct signaling pathway and that novobiocin and butyrate can be used as subsidiary drugs in preventing the growth of hepatoma.
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vacuole formation and cytokeratin rearrangement of hepatoma cells induced by Teleocidin are not associated with down regulation of protein kinase c
Cancer Research, 1991Co-Authors: Yoshiyasu Kaneko, Ayumi Tsukamoto, Kiyoshi KurokawaAbstract:: PLC/PRF/5 human hepatoma cells cultured with Teleocidin reduced the rate of cell proliferation and were transformed into large cells with many vacuole-like subcellular structures. In these vacuolated cells, the protein content per cell increased without changing the total cellular protein synthesis. Cytokeratin was one of the proteins which increased quantitatively. This intermediate filament formed fibrous network structures throughout the enlarged cytoplasm. The assembly of other cytoskeletal proteins such as actin, tubulin, and vimentin was not altered remarkably, suggesting that Teleocidin morphologically transformed the hepatoma cells by changing the assembly of cytokeratin protein selectively. On the other hand, the alterations of cell proliferation, cell morphology, and cytokeratin assembly induced by Teleocidin were not associated with either down-regulation of protein kinase C or reduced number of epidermal growth factor receptors. In addition, these Teleocidin effects were not mimicked by the protein kinase C agonist 1-oleoyl-2-acetylglycerol or inhibited by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. From these results it can be speculated that the morphological transformation and reduced cell proliferation induced by Teleocidin may be mediated by still unknown mechanisms unrelated to protein kinase C.
Koichi Shudo - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and stereochemistry of indolactam-v, an active fragment of Teleocidins. Structural requirements for tumor-promoting activity
Tetrahedron, 2001Co-Authors: Yasuyuki Endo, Koichi Shudo, Akiko Itai, Masashi Hasegawa, Shin-ichiro SakaiAbstract:Abstract (-)-Indolactam-V, which is an active fragment of the potent tumor promoters Teleocidins and has also been isolated as a Streptoverticillium metabolite, has been synthesized starting from 4-nitrogramine. The absolute stereochemistry of (-)-indolactam-V has been determined to be (9S, 12S), which suggests that Teleocidins and related compounds are biosynthesized from L-amino acids. Three unnatural diastereoisomers were also synthesized. The NMR spectra of (-)- and (±)-indolactam-V and its derivatives showed that they exist in two conformational states in solution. The structures of the two conformers were deduced from the chemical shifts, coupling constants and nuclear Overhauser effects to be SOFA and TWIST form which are characterized by trans and cis amide bonds, respectively. The calculated ratio of the two conformers was consistent with the observed ratio. The correct relative stereochemistry is shown in reference 11. The numbering system of Teleocidin derivatives is defined in the following order of preference; the indole ring, the ninemembered ring and the other substituents.10
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twist form of Teleocidin derivatives is active in in vivo tumor promotion by benzolactam v8 310
Biological & Pharmaceutical Bulletin, 1998Co-Authors: Sachiko Okabe, Masami Suganuma, Yasuyuki Endo, Koichi Shudo, Naoko Sueoka, Atsumasa Komori, Hirota FujikiAbstract:: Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to tumor promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and Teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and Teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and Teleocidin B-4, induced tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of Teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic tumor promoter designed from data obtained using the receptor cavity model of TPA-type tumor promoters.
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clarification of the binding mode of Teleocidin and benzolactams to the cys2 domain of protein kinase cδ by synthesis of hydrophobically modified Teleocidin mimicking benzolactams and computational docking simulation
Journal of Medicinal Chemistry, 1998Co-Authors: Yasuyuki Endo, Michihiro Ohno, Shunji Takehana, Paul E Driedger, Silvia Stabel, Miho Yamada Mizutani, Nobuo Tomioka, Akiko Itai, Koichi ShudoAbstract:Phorbol esters (12-O-tetradecanoylphorbol 13-acetate; TPA) and Teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. The benzolactam 5, with an eight-membered lactam ring and benzene ring instead of the nine-membered lactam ring and indole ring of Teleocidins, reproduces the active ring conformation and biological activities of Teleocidins. Herein we describe the synthesis of benzolactams with hydrophobic substituents at various positions. Structure−activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also computationally simulated the docking of Teleocidin and the modified benzolactam molecules to the Cys2 domain structure observed in the c...
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synthesis conformation and biological activity of Teleocidin mimics benzolactams a clarification of the conformational flexibility problem in structure activity studies of Teleocidins
Journal of the American Chemical Society, 1996Co-Authors: Yasuyuki Endo, Michihiro Ohno, Masaaki Hirano, And Akiko Itai, Koichi ShudoAbstract:Tumor-promoter Teleocidins and their active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis−trans isomerization of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring of indolactams is replaced with a benzene ring, were designed and synthesized in an attempt to reproduce the active conformation of Teleocidins. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benzolactam-V9 and -V10) exist exclusively in the sofa form in solution. The stronger biological activity of benzolactam-V-8-310 than that of indolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differentiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of Teleocidins.
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Synthesis, Conformation, and Biological Activity of Teleocidin Mimics, Benzolactams. A Clarification of the Conformational Flexibility Problem in Structure−Activity Studies of Teleocidins
Journal of the American Chemical Society, 1996Co-Authors: Yasuyuki Endo, Michihiro Ohno, Masaaki Hirano, And Akiko Itai, Koichi ShudoAbstract:Tumor-promoter Teleocidins and their active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis−trans isomerization of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring of indolactams is replaced with a benzene ring, were designed and synthesized in an attempt to reproduce the active conformation of Teleocidins. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benzolactam-V9 and -V10) exist exclusively in the sofa form in solution. The stronger biological activity of benzolactam-V-8-310 than that of indolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differentiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of Teleocidins.
Yasuyuki Endo - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and stereochemistry of indolactam-v, an active fragment of Teleocidins. Structural requirements for tumor-promoting activity
Tetrahedron, 2001Co-Authors: Yasuyuki Endo, Koichi Shudo, Akiko Itai, Masashi Hasegawa, Shin-ichiro SakaiAbstract:Abstract (-)-Indolactam-V, which is an active fragment of the potent tumor promoters Teleocidins and has also been isolated as a Streptoverticillium metabolite, has been synthesized starting from 4-nitrogramine. The absolute stereochemistry of (-)-indolactam-V has been determined to be (9S, 12S), which suggests that Teleocidins and related compounds are biosynthesized from L-amino acids. Three unnatural diastereoisomers were also synthesized. The NMR spectra of (-)- and (±)-indolactam-V and its derivatives showed that they exist in two conformational states in solution. The structures of the two conformers were deduced from the chemical shifts, coupling constants and nuclear Overhauser effects to be SOFA and TWIST form which are characterized by trans and cis amide bonds, respectively. The calculated ratio of the two conformers was consistent with the observed ratio. The correct relative stereochemistry is shown in reference 11. The numbering system of Teleocidin derivatives is defined in the following order of preference; the indole ring, the ninemembered ring and the other substituents.10
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twist form of Teleocidin derivatives is active in in vivo tumor promotion by benzolactam v8 310
Biological & Pharmaceutical Bulletin, 1998Co-Authors: Sachiko Okabe, Masami Suganuma, Yasuyuki Endo, Koichi Shudo, Naoko Sueoka, Atsumasa Komori, Hirota FujikiAbstract:: Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to tumor promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and Teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and Teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and Teleocidin B-4, induced tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of Teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic tumor promoter designed from data obtained using the receptor cavity model of TPA-type tumor promoters.
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clarification of the binding mode of Teleocidin and benzolactams to the cys2 domain of protein kinase cδ by synthesis of hydrophobically modified Teleocidin mimicking benzolactams and computational docking simulation
Journal of Medicinal Chemistry, 1998Co-Authors: Yasuyuki Endo, Michihiro Ohno, Shunji Takehana, Paul E Driedger, Silvia Stabel, Miho Yamada Mizutani, Nobuo Tomioka, Akiko Itai, Koichi ShudoAbstract:Phorbol esters (12-O-tetradecanoylphorbol 13-acetate; TPA) and Teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. The benzolactam 5, with an eight-membered lactam ring and benzene ring instead of the nine-membered lactam ring and indole ring of Teleocidins, reproduces the active ring conformation and biological activities of Teleocidins. Herein we describe the synthesis of benzolactams with hydrophobic substituents at various positions. Structure−activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also computationally simulated the docking of Teleocidin and the modified benzolactam molecules to the Cys2 domain structure observed in the c...
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synthesis conformation and biological activity of Teleocidin mimics benzolactams a clarification of the conformational flexibility problem in structure activity studies of Teleocidins
Journal of the American Chemical Society, 1996Co-Authors: Yasuyuki Endo, Michihiro Ohno, Masaaki Hirano, And Akiko Itai, Koichi ShudoAbstract:Tumor-promoter Teleocidins and their active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis−trans isomerization of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring of indolactams is replaced with a benzene ring, were designed and synthesized in an attempt to reproduce the active conformation of Teleocidins. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benzolactam-V9 and -V10) exist exclusively in the sofa form in solution. The stronger biological activity of benzolactam-V-8-310 than that of indolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differentiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of Teleocidins.
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Synthesis, Conformation, and Biological Activity of Teleocidin Mimics, Benzolactams. A Clarification of the Conformational Flexibility Problem in Structure−Activity Studies of Teleocidins
Journal of the American Chemical Society, 1996Co-Authors: Yasuyuki Endo, Michihiro Ohno, Masaaki Hirano, And Akiko Itai, Koichi ShudoAbstract:Tumor-promoter Teleocidins and their active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis−trans isomerization of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring of indolactams is replaced with a benzene ring, were designed and synthesized in an attempt to reproduce the active conformation of Teleocidins. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benzolactam-V9 and -V10) exist exclusively in the sofa form in solution. The stronger biological activity of benzolactam-V-8-310 than that of indolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differentiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of Teleocidins.
Hirota Fujiki - One of the best experts on this subject based on the ideXlab platform.
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twist form of Teleocidin derivatives is active in in vivo tumor promotion by benzolactam v8 310
Biological & Pharmaceutical Bulletin, 1998Co-Authors: Sachiko Okabe, Masami Suganuma, Yasuyuki Endo, Koichi Shudo, Naoko Sueoka, Atsumasa Komori, Hirota FujikiAbstract:: Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to tumor promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and Teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and Teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and Teleocidin B-4, induced tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of Teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic tumor promoter designed from data obtained using the receptor cavity model of TPA-type tumor promoters.
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comparison of 12 o tetradecanoylphorbol 13 acetate and Teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and skin tumor promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Xiao Jing Wang, Susan E Walker, Linda M Beltran, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and Teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote skin tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting skin tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, Teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting skin tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and Teleocidin, this mouse strain was still highly resistant to skin tumor promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of skin tumor promoters, including the Teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall promotion responsiveness between SENCAR and C57BL/6 mice with other classes of tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to skin tumor promotion by diverse promoting stimuli.
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Absence of Synergistic Effects on Tumor Promotion in CD-1 Mouse Skin by Simultaneous Applications of Two Different Types of Tumor Promoters, Okadaic Acid and Teleocidin
Cancer Research, 1993Co-Authors: Masami Suganuma, Jun Yatsunami, Seiji Yoshizawa, Sachiko Okabe, Hirota FujikiAbstract:Abstract Okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A, and Teleocidin, an activator of protein kinase C, are both potent tumor promoters on mouse skin. The effects of simultaneous treatment of the two different types of tumor promoters on tumor promotion as well as on their biochemical activities were studied. Three independent experiments with different doses of tumor promoters revealed that simultaneous repeated applications of okadaic acid and Teleocidin did not induce any synergistic or additive effects on tumor promotion in mouse skin initiated with 7,12-dimethylbenz( a )anthracene (DMBA). In Experiment 1, the group treated with a single application of DMBA, followed by repeated applications of 1.0 µg (1.2 nmol) okadaic acid and 2.5 µg (5.7 nmol) Teleocidin, resulted in 64.3% tumor-bearing mice at week 20. But the groups treated with DMBA plus okadaic acid or DMBA plus Teleocidin gave 73.3% and 71.4%, respectively. The biochemical activities were studied by means of induction of ornithine decarboxylase in mouse skin and protein phosphorylation in the cells. Simultaneous application of okadaic acid at three different doses with Teleocidin did not induce ornithine decarboxylase activity synergistically or additively. Phosphorylation of proteins, cytokeratins, or heat shock protein 27 was not synergistically increased in human keratinocytes treated with okadaic acid and Teleocidin, although the cotreatment in a cell-free system synergistically increased protein phosphorylation. Thus, the absence of synergistic effects on tumor promotion in mouse skin was also confirmed in two systems, induction of ornithine decarboxylase in mouse skin and protein phosphorylation in human keratinocytes. The effect of cotreatment of okadaic acid and Teleocidin is discussed at the molecular level.
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pendolmycin a new tumor promoter of the Teleocidin a class on skin of cd 1 mice
Japanese Journal of Cancer Research, 1991Co-Authors: Shinji Nishiwaki, Masami Suganuma, Michie Nakayasu, Hideaki Muratake, Kazuaki Okabe, Hirota Fujiki, Seiji Yoshizawa, Sachiko Okabe, Hiroko Furuyasuguri, Mitsutaka NatsumeAbstract:: Pendolmycin, isolated from Nocardiopsis, is a compound structurally similar to Teleocidin A, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters. Pendolmycin has a C5 dimethyl allyl group attached to C-7 of (-)-indolactam-V, whereas Teleocidin A has a C10 linalyl group attached to the molecule. The structure-activity relationships of a hydrophobic moiety attached to (-)-indolactam-V were studied in four compounds, (-)-indolactam-V, pendolmycin, Teleocidin A and newly synthesized 7-(nerolidyl)-(-)-indolactam-V in tests on inhibition of the specific [3H]TPA binding to a particulate fraction of mouse skin, activation of protein kinase C and induction of both adhesion of HL-60 cells and ornithine decarboxylase in mouse skin. The potencies of the compounds for these activities increased mainly depending on the length of the hydrophobic group. Pendolmycin had a tumor-promoting activity on mouse skin initiated with a single application of 7,12-dimethyl-benz[a]anthracene, and its potency was just between those of (-)-indolactam-V and Teleocidin A. The role of the hydrophobic moiety is discussed with particular emphasis on the results obtained with 7-(nerolidyl)-(-)-indolactam-V.
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Tumor-promoting activity of staurosporine, a protein kinase inhibitor on mouse skin.
Cancer Research, 1990Co-Authors: Shigeru Yoshizawa, Hiroko Suguri, Rie Matsushima, Masami Suganuma, Michie Nakayasu, Hirota Fujiki, Takashi SugimuraAbstract:Staurosporine, which is a potent inhibitor of protein kinases, such as protein kinase C, inhibited both inductions of adhesion of human promyelocytic leukemia cells (50% effective dose = 9.0 nm) and Epstein-Barr virus early antigen in Raji cells (50% effective dose = 3.4 nm) by Teleocidin. However, staurosporine induced irritation on mouse ear and histidine decarboxylase activity in mouse skin. It did not induce ornithine decarboxylase activity in mouse epidermis. The two-stage carcinogenesis experiments of staurosporine were carried out at two different doses. Experiment 1 revealed that the group treatment with a single application of 100 µg of 7,12-dimethylbenz( a )anthracene, followed by repeated applications of 50 µg of staurosporine, resulted in 85.7% of tumor-bearing mice at Wk 30, whereas group treatment with staurosporine alone or 7,12-dimethylbenz( a )anthracene alone gave 6.7% and 0%, respectively. Experiment 2 showed that group treatment with 7,12-dimethylbenz( a )anthracene followed by applications of 10 µg of staurosporine resulted in 33% of tumor-bearing mice at Wk 30. In addition, staurosporine treatment reduced the percentages of tumor-bearing mice treated with Teleocidin from 100% to 67% in Wk 15. These results demonstrated that staurosporine is a weak tumor promoter of mouse skin compared with Teleocidin, but staurosporine has some potency to inhibit tumor promotion by Teleocidin.
Yoshiyasu Kaneko - One of the best experts on this subject based on the ideXlab platform.
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involvement of down regulation resistant protein kinase c in Teleocidin inhibition of cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin in human hepatoma cells
Cancer Letters, 1993Co-Authors: Yoshiyasu Kaneko, Ayumi Tsukamoto, Kiyoshi KurokawaAbstract:Abstract Teleocidin, a phorbol ester-type tumor promoter, inhibits cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin in PLC/PRF/5 hepatoma cells. These inhibitory effects of Teleocidin were observed even after a prolonged exposure of the hepatoma cells to this promoter, suggesting the presence of down-regulation-resistant protein kinase C in this hepatoma cell line. Column chromatography of cytosolic fractions showed three separate peaks of protein kinase C activity, two being down-regulation-sensitive while one was down-regulation-resistant. This down-regulation-resistant PKC is suggested to be responsible for the inhibitory effect of Teleocidin on cell proliferation and calcium mobilization induced by epidermal growth factor and vasopressin.
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thapsigargin an inhibitor of endoplasmic reticulum ca2 atpase enhances c fos expression but antagonizes vacuole formation of human hepatoma cells induced by Teleocidin
Biochimica et Biophysica Acta, 1993Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Teleocidin, a phorbol ester-type tumor promoter, enhanced actin redistribution, vacuole formation and c-fos expression of PLC/PRF/5 hepatoma cells. This tumor promoter also inhibited calcium mobilization induced by epidermal growth factor (EGF). Thapsigargin, a specific inhibitor of endoplasmic reticulum Ca2+-ATPase, elevated cytosolic calcium, enhanced c-fos expression and antagonized the vacuole formation induced by Teleocidin without interfering with actin redistribution and Lucifer yellow uptake. On the other hand, a calcium ionophore ionomycin elevated both cytosolic Ca2+ and c-fos mRNA but could not antagonize the vacuole formation induced by Teleocidin. From these results it was speculated that the Ca2+ leak from the endoplasmic reticulum rather than the elevation of cytosolic Ca2+ appeared to be responsible for the specific inhibition of vacuole formation by thapsigargin.
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thapsigargin an inhibitor of endoplasmic reticulum ca2 atpase antagonizes cytokeratin assembly of human hepatoma cells induced by Teleocidin
International Hepatology Communications, 1993Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Abstract Teleocidin, a phorbol ester-type of tumor promoter markedly enhanced cytokeratin assembly of PLC/PRF/5 hepatoma cells. Thapsigargin, a non-phorbol ester-type tumor promoter which specifically inhibited endoplasmic reticulum Ca 2+ -ATPase, elevated cytosolic calcium and antagonized the cytokeratin assembly induced by Teleocidin. A calcium ionophore ionomycin mimicked the effect of thapsigargin, suggesting that elevated cytosolic calcium appeared to be responsible for the antagonistic action of thapsigargin on the cytokeratin assembly.
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novobiocin modulates cytokeratin assembly and differentiation of human hepatoma cells induced by butyrate and Teleocidin
Cancer Letters, 1991Co-Authors: Ayumi Tsukamoto, Yoshiyasu Kaneko, Kiyoshi KurokawaAbstract:Abstract A differentiation inducer butyrate and a tumor promoter Teleocidin had inhibitory effects on the proliferation of PLC/PRF/5 hepatoma. Both of these reagents stimulated the production of procollagen type III peptide, enhanced the cytokeratin assembly and altered the morphological appearance. Novobiocin, a topoisomerase II inhibitor, enhanced the cytokeratin assembly induced by butyrate but antagonized that induced by Teleocidin without changing the expression and the phosphorylation state of cytokeratin proteins. In addition, novobiocin acted synergistically with butyrate but not with Teleocidin in stimulating the procollagen production and the acetate uptake. These results suggest that butyrate and Teleocidin induce cell differentiation via distinct signaling pathway and that novobiocin and butyrate can be used as subsidiary drugs in preventing the growth of hepatoma.
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vacuole formation and cytokeratin rearrangement of hepatoma cells induced by Teleocidin are not associated with down regulation of protein kinase c
Cancer Research, 1991Co-Authors: Yoshiyasu Kaneko, Ayumi Tsukamoto, Kiyoshi KurokawaAbstract:: PLC/PRF/5 human hepatoma cells cultured with Teleocidin reduced the rate of cell proliferation and were transformed into large cells with many vacuole-like subcellular structures. In these vacuolated cells, the protein content per cell increased without changing the total cellular protein synthesis. Cytokeratin was one of the proteins which increased quantitatively. This intermediate filament formed fibrous network structures throughout the enlarged cytoplasm. The assembly of other cytoskeletal proteins such as actin, tubulin, and vimentin was not altered remarkably, suggesting that Teleocidin morphologically transformed the hepatoma cells by changing the assembly of cytokeratin protein selectively. On the other hand, the alterations of cell proliferation, cell morphology, and cytokeratin assembly induced by Teleocidin were not associated with either down-regulation of protein kinase C or reduced number of epidermal growth factor receptors. In addition, these Teleocidin effects were not mimicked by the protein kinase C agonist 1-oleoyl-2-acetylglycerol or inhibited by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. From these results it can be speculated that the morphological transformation and reduced cell proliferation induced by Teleocidin may be mediated by still unknown mechanisms unrelated to protein kinase C.
