The Experts below are selected from a list of 60 Experts worldwide ranked by ideXlab platform

M Koyama - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of multidrug resistance by a new Staurosporine Derivative na 382 in vitro and in vivo
    Cancer Research, 1993
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kenzo Takagi, Kosei Inoko, Shinji Kajita, Takaaki Hasegawa, M Koyama
    Abstract:

    Abstract The effects of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on multidrug resistance in tumor cells were investigated. Protein kinase-inhibitory activity of NA-382 was lower but more selective to Ca2+/phospholipid-dependent protein kinase than that of Staurosporine. NA-382 at noncytotoxic concentrations effectively reversed in vitro multidrug resistance of Adriamycin-resistant P388 (P388/ADR) cells, without influencing the drug sensitivity of sensitive P388 cells. NA-382 inhibited extrusion of vinblastine (VBL) and increased intracellular accumulation of VBL, more in P388/ADR cells than in sensitive P388 cells, with higher potency than Staurosporine. This compound also reduced VBL resistance of other multidrug-resistant cell lines, AH66 and K562/ADR, by inhibiting VBL efflux and promoting VBL accumulation. NA-382 also dose dependently potentiated the effects of VBL and Adriamycin in P388/ADR-bearing mice. The toxicity of Staurosporine was too high to use the combination with VBL in vitro and in vivo. NA-382 accumulated VBL in P388/ADR cells even after desensitization of Ca2+/phospholipid-dependent protein kinase by treatment with 12-O-tetradecanoylphorbol-13-acetate for 18 h, while being suppressed by 12-O-tetradecanoylphorbol-13-acetate added simultaneously or shortly before NA-382. Both Staurosporine and NA-382 inhibited the photolabeling of [3H]azidopine on Mr 140,000 P-glycoprotein in the plasma membrane from P388/ADR cells. These results indicate that this new Staurosporine analogue, NA-382, reverses multidrug resistance by directly inhibiting the drug binding to P-glycoprotein, but not by Ca2+/phospholipid-dependent protein kinase inhibitory action.

  • reversal of vinblastine resistance by a new Staurosporine Derivative na 382 in p388adr cells
    Cancer Letters, 1992
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kohsei Inoko, Kenzo Takagi, M Koyama
    Abstract:

    Abstract Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca 2+ phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of Staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of Staurosporine. NA-382 was less toxic to P388 cells and at a noncytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 ( P388 ADR ) cells without influence on the effect of VBL on the parental P388 S cells. However, the cytotoxicity of Staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388 ADR with higher potency than Staurosporine. Both compounds inhibited the photolabeling of [ 3 H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a Staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

Kenichi Miyamoto - One of the best experts on this subject based on the ideXlab platform.

  • antitumour effects and pharmacokinetics of combination of vinblastine with a Staurosporine Derivative na 382 in p388 adr bearing mice
    Journal of Pharmacy and Pharmacology, 2011
    Co-Authors: Kenichi Miyamoto, Keiko Takeda, Kenjiro Koga, Taeyuki Ohshima, Shinya Wakusawa
    Abstract:

    The effects of a Staurosporine Derivative, N-ethoxycarbonyl-7-oxoStaurosporine (NA-382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug-resistant P388/ADR-bearing mice. At first, the in-vitro experiments indicated that NA-382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 μ kg−1) into P388/ADR-bearing mice, NA-382 in a suspension form (10 mg kg−1) prolonged the life-span of the mice near to that of P388/S-bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg−1) barely affected the in-vivo antitumour effect of vinblastine. When simultaneously administered with vinblastine to P388/ADR-bearing mice, NA-382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time-intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid. This study indicates that NA-382 is more effective against multidrug-resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug-resistant tumours.

  • inhibition of multidrug resistance by a new Staurosporine Derivative na 382 in vitro and in vivo
    Cancer Research, 1993
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kenzo Takagi, Kosei Inoko, Shinji Kajita, Takaaki Hasegawa, M Koyama
    Abstract:

    Abstract The effects of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on multidrug resistance in tumor cells were investigated. Protein kinase-inhibitory activity of NA-382 was lower but more selective to Ca2+/phospholipid-dependent protein kinase than that of Staurosporine. NA-382 at noncytotoxic concentrations effectively reversed in vitro multidrug resistance of Adriamycin-resistant P388 (P388/ADR) cells, without influencing the drug sensitivity of sensitive P388 cells. NA-382 inhibited extrusion of vinblastine (VBL) and increased intracellular accumulation of VBL, more in P388/ADR cells than in sensitive P388 cells, with higher potency than Staurosporine. This compound also reduced VBL resistance of other multidrug-resistant cell lines, AH66 and K562/ADR, by inhibiting VBL efflux and promoting VBL accumulation. NA-382 also dose dependently potentiated the effects of VBL and Adriamycin in P388/ADR-bearing mice. The toxicity of Staurosporine was too high to use the combination with VBL in vitro and in vivo. NA-382 accumulated VBL in P388/ADR cells even after desensitization of Ca2+/phospholipid-dependent protein kinase by treatment with 12-O-tetradecanoylphorbol-13-acetate for 18 h, while being suppressed by 12-O-tetradecanoylphorbol-13-acetate added simultaneously or shortly before NA-382. Both Staurosporine and NA-382 inhibited the photolabeling of [3H]azidopine on Mr 140,000 P-glycoprotein in the plasma membrane from P388/ADR cells. These results indicate that this new Staurosporine analogue, NA-382, reverses multidrug resistance by directly inhibiting the drug binding to P-glycoprotein, but not by Ca2+/phospholipid-dependent protein kinase inhibitory action.

  • reversal of vinblastine resistance by a new Staurosporine Derivative na 382 in p388adr cells
    Cancer Letters, 1992
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kohsei Inoko, Kenzo Takagi, M Koyama
    Abstract:

    Abstract Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca 2+ phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of Staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of Staurosporine. NA-382 was less toxic to P388 cells and at a noncytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 ( P388 ADR ) cells without influence on the effect of VBL on the parental P388 S cells. However, the cytotoxicity of Staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388 ADR with higher potency than Staurosporine. Both compounds inhibited the photolabeling of [ 3 H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a Staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

Shinya Wakusawa - One of the best experts on this subject based on the ideXlab platform.

  • antitumour effects and pharmacokinetics of combination of vinblastine with a Staurosporine Derivative na 382 in p388 adr bearing mice
    Journal of Pharmacy and Pharmacology, 2011
    Co-Authors: Kenichi Miyamoto, Keiko Takeda, Kenjiro Koga, Taeyuki Ohshima, Shinya Wakusawa
    Abstract:

    The effects of a Staurosporine Derivative, N-ethoxycarbonyl-7-oxoStaurosporine (NA-382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug-resistant P388/ADR-bearing mice. At first, the in-vitro experiments indicated that NA-382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 μ kg−1) into P388/ADR-bearing mice, NA-382 in a suspension form (10 mg kg−1) prolonged the life-span of the mice near to that of P388/S-bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg−1) barely affected the in-vivo antitumour effect of vinblastine. When simultaneously administered with vinblastine to P388/ADR-bearing mice, NA-382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time-intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid. This study indicates that NA-382 is more effective against multidrug-resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug-resistant tumours.

  • inhibition of multidrug resistance by a new Staurosporine Derivative na 382 in vitro and in vivo
    Cancer Research, 1993
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kenzo Takagi, Kosei Inoko, Shinji Kajita, Takaaki Hasegawa, M Koyama
    Abstract:

    Abstract The effects of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on multidrug resistance in tumor cells were investigated. Protein kinase-inhibitory activity of NA-382 was lower but more selective to Ca2+/phospholipid-dependent protein kinase than that of Staurosporine. NA-382 at noncytotoxic concentrations effectively reversed in vitro multidrug resistance of Adriamycin-resistant P388 (P388/ADR) cells, without influencing the drug sensitivity of sensitive P388 cells. NA-382 inhibited extrusion of vinblastine (VBL) and increased intracellular accumulation of VBL, more in P388/ADR cells than in sensitive P388 cells, with higher potency than Staurosporine. This compound also reduced VBL resistance of other multidrug-resistant cell lines, AH66 and K562/ADR, by inhibiting VBL efflux and promoting VBL accumulation. NA-382 also dose dependently potentiated the effects of VBL and Adriamycin in P388/ADR-bearing mice. The toxicity of Staurosporine was too high to use the combination with VBL in vitro and in vivo. NA-382 accumulated VBL in P388/ADR cells even after desensitization of Ca2+/phospholipid-dependent protein kinase by treatment with 12-O-tetradecanoylphorbol-13-acetate for 18 h, while being suppressed by 12-O-tetradecanoylphorbol-13-acetate added simultaneously or shortly before NA-382. Both Staurosporine and NA-382 inhibited the photolabeling of [3H]azidopine on Mr 140,000 P-glycoprotein in the plasma membrane from P388/ADR cells. These results indicate that this new Staurosporine analogue, NA-382, reverses multidrug resistance by directly inhibiting the drug binding to P-glycoprotein, but not by Ca2+/phospholipid-dependent protein kinase inhibitory action.

  • reversal of vinblastine resistance by a new Staurosporine Derivative na 382 in p388adr cells
    Cancer Letters, 1992
    Co-Authors: Kenichi Miyamoto, Shinya Wakusawa, Kohsei Inoko, Kenzo Takagi, M Koyama
    Abstract:

    Abstract Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-Staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca 2+ phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of Staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of Staurosporine. NA-382 was less toxic to P388 cells and at a noncytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 ( P388 ADR ) cells without influence on the effect of VBL on the parental P388 S cells. However, the cytotoxicity of Staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388 ADR with higher potency than Staurosporine. Both compounds inhibited the photolabeling of [ 3 H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a Staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

Urs Regenass - One of the best experts on this subject based on the ideXlab platform.

  • the protein kinase c inhibitor cgp 41251 a Staurosporine Derivative with antitumor activity reverses multidrug resistance
    International Journal of Cancer, 1994
    Co-Authors: I Utz, S Hofer, Urs Regenass, Wolfgang Hilbe, Josef Thaler, Hans Grunicke, Johann Hofmann
    Abstract:

    Multidrug resistance (MDR) is frequently associated with overexpression of a 170-kDa P-glycoprotein (Pgp). Data suggest altered protein kinase C (PKC) activity in cells expressing the multidrug-resistant phenotype. The Staurosporine Derivative CCP A1251, an experimental anticancer drug, has been shown to exert selectivity for inhibition of protein kinase C activity and to exhibit antitumor activity in Wtro and in vivo. Here we show that CGP A1251 is also able to reverse MDR. After treatment of the mult id rug-resistant human lymphoblastoid cell line CCRF-VCR1000 with 500 nM Adriamydn, cell proliferation was reduced to 81% of untreated controls. A combination of 500 nM Adriamydn with a non-toxic concentration of 150 nM CGP 41251 (IC50 for inhibition of cell proliferation 420 nM CGP 41251) inhibits cell proliferation of CCRF-VCR1000 cells to 29% of untreated controls. In sensitive CCRF-CEM cells no enhancement of Adriamycin-induced cytotoxicity was observed upon addition of 150 nM CGP 41251. Strong synergism of the inhibition of cell proliferation was also observed after concomitant treatment of KB-851 I cells with CGP 41251 and Vinblas-tine or Adriamydn. Drug-sensitive KB-31 cells could not be further sensitized to Adriamycin or Vinblastine with CGP 41251 doses above 100 nM. Pretreatment with 50-1000 nM CGP 41251 for 30 min led to a dose-dependent increase in the intracellular accumulation of rhodamine 123, a substrate of P-glycoprotein. Treatment of multidrug-resistant CCRF-VCR1000 cells with CGP 41251 for 10 min was sufficient to inhibit the efflux of rhodamine 123. Preincubation with CGP 41251 for 12 or 24 hr did not alter multidrug resistance gene (mdrl)-mRNA levels. CGP 41251, a drug with antitumor efficacy in experimental systems, might offer an attractive combination partner for the treatment of tumors expressing the MDR phenotype. © Wiley-Liss, Inc.

  • differential inhibition of the epidermal growth factor platelet derived growth factor and protein kinase c mediated signal transduction pathways by the Staurosporine Derivative cgp 41251
    Cancer Research, 1992
    Co-Authors: Elisabeth Andrejauskasbuchdunger, Urs Regenass
    Abstract:

    The microbial alkaloid Staurosporine is a potent but nonselective inhibitor of protein kinases. The Derivative CGP 41251 has been shown to exert a high degree of selectivity for inhibition of protein kinase C activity. Both compounds are powerful inhibitors of proliferation of both normal and transformed cells in vitro and exert antitumor efficacy in vivo. In this work we have studied the mode of action of these compounds by analyzing their effects on early events in the induction of proliferation by different growth stimuli. Both drugs blocked the phorbol ester-induced expression of the c-fos proto-oncogene. The effect of CGP 41251 was reversible, since its removal led to a normal expression of c-fos mRNA in response to phorbol 12-myristate 13-acetate. Submicromolar concentrations of CGP 41251 and Staurosporine directly inhibited both the platelet-derived growth factor (PDGF) receptor autophosphorylation and the c-fos mRNA expression induced by PDGF stimulation of intact BALB/c 3T3 cells. In contrast, ligand-induced epidermal growth factor receptor autokinase activity in A431 carcinoma cells and epidermal growth factor-dependent c-fos mRNA expression were relatively insensitive to inhibition by CGP 41251. Staurosporine suppressed signal generation by the epidermal growth factor receptor by reducing overall levels of the receptor. We conclude that CGP 41251 is a potent reversible inhibitor of protein kinase C and PDGF-mediated signal transduction. It inhibits the kinase activity of both protein kinase C and the PDGF receptor tyrosine kinase and the subsequent signaling cascade. The broad inhibition of kinases by Staurosporine is also reflected at the cellular level and might contribute to the high toxicity of this compound, in comparison to CGP 41251.

H Keller - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells
    2013
    Co-Authors: A. Zimmermann, H Keller
    Abstract:

    Summary The structure/activity relationship of the protein kinase inhibitors, Staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (IDm of about 6.0 x 10-8 M) as well as spontaneous and colchicine-stimulated locomotion at 10-7 M. K 252a suppresses cell polarity (IDm of about 4.5 x 10-6 M) and inhibits spontaneous and colchicinestimulated locomotion at I0-I M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a Staurosporine Derivative with a much higher specificity for protein kinase C (PKC) than Staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K 252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotidedependent protein kinases, and CGP 42700, an inactive Staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion. Several mechanisms are instrumental in invasion and metastasis

  • effects of Staurosporine k 252a and other structurally related protein kinase inhibitors on shape and locomotion of walker carcinosarcoma cells
    British Journal of Cancer, 1992
    Co-Authors: A. Zimmermann, H Keller
    Abstract:

    The structure/activity relationship of the protein kinase inhibitors, Staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a Staurosporine Derivative with a much higher specificity for protein kinase C (PKC) than Staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive Staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.