2004
Hoferová, Zuzana; Soucek, Karel; Hofmanová, Jirina; Hofer, Michael; Chramostová, Katerina; Fedorocko, Peter; Kozubik, Alois
In vitro proliferation of fibrosarcoma cells depends on intact functions of lipoxygenases and cytochrome P-450-monooxygenase. Journal Article
In: Cancer investigation, vol. 22, no. 2, pp. 234–247, 2004, ISSN: 0735-7907, (Place: England).
Abstract | Links | BibTeX | Tags: Animals, Apoptosis, Arachidonic Acid/antagonists & inhibitors/metabolism/*pharmacology, Cell Cycle/*physiology, Cultured, Cytochrome P-450 Enzyme System/*pharmacology, Enzyme Inhibitors/pharmacology, Fibrosarcoma/*pathology/veterinary, Lipoxygenase/*pharmacology, Mice, Tumor Cells
@article{hoferova_vitro_2004,
title = {In vitro proliferation of fibrosarcoma cells depends on intact functions of lipoxygenases and cytochrome P-450-monooxygenase.},
author = {Zuzana Hoferová and Karel Soucek and Jirina Hofmanová and Michael Hofer and Katerina Chramostová and Peter Fedorocko and Alois Kozubik},
doi = {10.1081/cnv-120030212},
issn = {0735-7907},
year = {2004},
date = {2004-01-01},
journal = {Cancer investigation},
volume = {22},
number = {2},
pages = {234–247},
abstract = {Proliferation of mouse fibrosarcoma cells G:5:113 was studied in vitro after affecting particular pathways of arachidonic acid metabolism by selected inhibitors. After 48 hours of cultivation with nonspecific lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA) and esculetin; a specific 12-lipoxygenase inhibitor, baicalein; and inhibitor of five-lipoxygenase activating protein, MK-886, markedly suppressed the number of cells and induced significant changes in cell cycle distribution in a dose-dependent manner. While proadifen, an inhibitor of cytochrome P-450-monooxygenase, applied in low concentrations, increased the cell number, at higher concentrations, it inhibited cell proliferation and significantly changed the cell cycle. Cyclooxygenase inhibitors, ibuprofen, flurbiprofen, and diclofenac suppressed cell numbers only moderately without any changes in the cell cycle. The occurrence of apoptosis was not significant for any of the selected drugs in comparison with untreated control cells. Moreover, not even one of the drugs caused the specific cleavage of poly (ADP-ribose) polymerase to the 89-kDa fragment, however, a decrease in total amount of this protein was observed after treatment with NDGA and esculetin. We conclude that the proliferation ability of fibrosarcoma cells G:5:113 in vitro depends on intact functions of 5-lipoxygenase, 12-lipoxygenase, and cytochrome P-450-monooxygenases, and that the effects of inhibitors do not include regulation of apoptosis.},
note = {Place: England},
keywords = {Animals, Apoptosis, Arachidonic Acid/antagonists & inhibitors/metabolism/*pharmacology, Cell Cycle/*physiology, Cultured, Cytochrome P-450 Enzyme System/*pharmacology, Enzyme Inhibitors/pharmacology, Fibrosarcoma/*pathology/veterinary, Lipoxygenase/*pharmacology, Mice, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
Proliferation of mouse fibrosarcoma cells G:5:113 was studied in vitro after affecting particular pathways of arachidonic acid metabolism by selected inhibitors. After 48 hours of cultivation with nonspecific lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA) and esculetin; a specific 12-lipoxygenase inhibitor, baicalein; and inhibitor of five-lipoxygenase activating protein, MK-886, markedly suppressed the number of cells and induced significant changes in cell cycle distribution in a dose-dependent manner. While proadifen, an inhibitor of cytochrome P-450-monooxygenase, applied in low concentrations, increased the cell number, at higher concentrations, it inhibited cell proliferation and significantly changed the cell cycle. Cyclooxygenase inhibitors, ibuprofen, flurbiprofen, and diclofenac suppressed cell numbers only moderately without any changes in the cell cycle. The occurrence of apoptosis was not significant for any of the selected drugs in comparison with untreated control cells. Moreover, not even one of the drugs caused the specific cleavage of poly (ADP-ribose) polymerase to the 89-kDa fragment, however, a decrease in total amount of this protein was observed after treatment with NDGA and esculetin. We conclude that the proliferation ability of fibrosarcoma cells G:5:113 in vitro depends on intact functions of 5-lipoxygenase, 12-lipoxygenase, and cytochrome P-450-monooxygenases, and that the effects of inhibitors do not include regulation of apoptosis.
2003
Bryja, Vítezslav; Sedlácek, Jirí; Zahradnícková, Eva; Sevcíková, Sabina; Pacherník, Jirí; Soucek, Karel; Hofmanová, Jirina; Kozubík, Alois; Smarda, Jan
Lipoxygenase inhibitors enhance tumor suppressive effects of jun proteins on v-myb-transformed monoblasts BM2. Journal Article
In: Prostaglandins & other lipid mediators, vol. 72, no. 3-4, pp. 131–145, 2003, ISSN: 1098-8823, (Place: United States).
Abstract | Links | BibTeX | Tags: *Genes, 11, 14-Eicosatetraynoic Acid/metabolism, 5, 8, Animals, Antioxidants/pharmacology, Apoptosis, Arachidonic Acids/metabolism, Cell Cycle/drug effects, Cell Division/*drug effects, Cells, Chickens, Cultured, Humans, Lipoxygenase Inhibitors/*pharmacology, Lipoxygenase/*metabolism, Masoprocol/pharmacology, Monocytes/cytology/*drug effects/physiology, myb, Proto-Oncogene Proteins c-jun/genetics/*metabolism, Umbelliferones/pharmacology
@article{bryja_lipoxygenase_2003,
title = {Lipoxygenase inhibitors enhance tumor suppressive effects of jun proteins on v-myb-transformed monoblasts BM2.},
author = {Vítezslav Bryja and Jirí Sedlácek and Eva Zahradnícková and Sabina Sevcíková and Jirí Pacherník and Karel Soucek and Jirina Hofmanová and Alois Kozubík and Jan Smarda},
doi = {10.1016/s1098-8823(03)00052-2},
issn = {1098-8823},
year = {2003},
date = {2003-11-01},
journal = {Prostaglandins & other lipid mediators},
volume = {72},
number = {3-4},
pages = {131–145},
abstract = {Inhibitors of arachidonic acid (AA) conversion were described as suppressors of proliferation and inducers of differentiation of various leukemic cells. Certain AA metabolites have been shown to cooperate with Jun proteins that are important factors controlling cell proliferation, differentiation and apoptosis. Using lipoxygenase (LOX) inhibitors of various specifity we studied possible participation of lipoxygenase pathway in regulation of proliferation and apoptosis of v-myb-transformed chicken monoblasts BM2 and its functional interaction with Jun proteins. We found that nordihydroguaiaretic acid (NDGA) and esculetin (Esc) negatively regulate proliferation of BM2 cells causing accumulation in either G0/G1-phase (nordihydroguaiaretic acid) or S-phase (esculetin) of the cell cycle. BM2 cells can be also induced to undergo growth arrest and partial differentiation by ectopic expression of Jun proteins. We demonstrated that lipoxygenase inhibitors further enforce tumor suppressive capabilities of Jun proteins by inducing either more efficient cell cycle block and/or apoptosis in BM2 cells. This suggests that there is a cross-talk between the lipoxygenase- and Jun-directed pathways in regulation of differentiation and proliferation of monoblastic cells. Thus pharmacologic agents that specifically block lipoxygenase-catalyzed activity and enforce the effects of differentiation-inducers may be important components in anti-tumor therapies.},
note = {Place: United States},
keywords = {*Genes, 11, 14-Eicosatetraynoic Acid/metabolism, 5, 8, Animals, Antioxidants/pharmacology, Apoptosis, Arachidonic Acids/metabolism, Cell Cycle/drug effects, Cell Division/*drug effects, Cells, Chickens, Cultured, Humans, Lipoxygenase Inhibitors/*pharmacology, Lipoxygenase/*metabolism, Masoprocol/pharmacology, Monocytes/cytology/*drug effects/physiology, myb, Proto-Oncogene Proteins c-jun/genetics/*metabolism, Umbelliferones/pharmacology},
pubstate = {published},
tppubtype = {article}
}
Inhibitors of arachidonic acid (AA) conversion were described as suppressors of proliferation and inducers of differentiation of various leukemic cells. Certain AA metabolites have been shown to cooperate with Jun proteins that are important factors controlling cell proliferation, differentiation and apoptosis. Using lipoxygenase (LOX) inhibitors of various specifity we studied possible participation of lipoxygenase pathway in regulation of proliferation and apoptosis of v-myb-transformed chicken monoblasts BM2 and its functional interaction with Jun proteins. We found that nordihydroguaiaretic acid (NDGA) and esculetin (Esc) negatively regulate proliferation of BM2 cells causing accumulation in either G0/G1-phase (nordihydroguaiaretic acid) or S-phase (esculetin) of the cell cycle. BM2 cells can be also induced to undergo growth arrest and partial differentiation by ectopic expression of Jun proteins. We demonstrated that lipoxygenase inhibitors further enforce tumor suppressive capabilities of Jun proteins by inducing either more efficient cell cycle block and/or apoptosis in BM2 cells. This suggests that there is a cross-talk between the lipoxygenase- and Jun-directed pathways in regulation of differentiation and proliferation of monoblastic cells. Thus pharmacologic agents that specifically block lipoxygenase-catalyzed activity and enforce the effects of differentiation-inducers may be important components in anti-tumor therapies.
Machala, Miroslav; Bláha, Ludek; Vondrácek, Jan; Trosko, James E.; Scott, Jacob; Upham, Brad L.
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 76, no. 1, pp. 102–111, 2003, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Blotting, Cell Line, Epidermal Growth Factor/toxicity, Epithelial Cells/drug effects/enzymology, Gap Junctions/*drug effects/enzymology, Liver/cytology, Mitogen-Activated Protein Kinases/metabolism, Polychlorinated Biphenyls/*toxicity, Rats, Signal Transduction/*drug effects, Sphingomyelin Phosphodiesterase/metabolism, src-Family Kinases/metabolism, Tetradecanoylphorbol Acetate/toxicity, Western
@article{machala_inhibition_2003,
title = {Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: inhibitory potencies and screening for potential mode(s) of action.},
author = {Miroslav Machala and Ludek Bláha and Jan Vondrácek and James E. Trosko and Jacob Scott and Brad L. Upham},
doi = {10.1093/toxsci/kfg209},
issn = {1096-6080 1096-0929},
year = {2003},
date = {2003-11-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {76},
number = {1},
pages = {102–111},
abstract = {Polychlorinated biphenyls (PCBs), a structurally diverse group of environmental pollutants, are effective promoters in two-stage cancer models, which implies that epigenetic mechanisms are involved. Inhibition of gap junctional intercellular communication (GJIC) belongs among critical epigenetic events of tumor promotion. We determined the relative potencies of a series of environmentally relevant PCB congeners to inhibit GJIC in vitro in a rat liver epithelial cell line with pluripotent oval cell characteristics. The nonplanar PCBs were potent inhibitors of GJIC, whereas the coplanar PCBs did not inhibit GJIC. We then compared the effects of the coplanar PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the noncoplanar PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) with effects of two model GJIC inhibitors, a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In contrast to TPA or EGF, PCB 153 elicited a long-term downregulation of GJIC (up to 48 h). Using Western blot analysis with phospho-specific antibodies, it was found that PCB 153, and not PCB 126, activated mitogen-activated protein kinases ERK1/2; however in contrast to TPA and EGF, this activation was observed at the time points subsequent to GJIC inhibition. Moreover, blocking of ERK1/2 activation did not prevent the GJIC inhibition induced by PCB 153. Therefore, additional intracellular signaling pathways potentially involved in the downregulation of GJIC by PCBs were screened by using specific chemical probes inhibiting serine/threonine kinases, tyrosine kinases, and phospholipases. The inhibition of diacylglycerol lipase partially blocked and the selective inhibition of Src kinases and phosphatidylcholine-specific phospholipase C (PC-PLC) completely blocked the inhibitory effects of the noncoplanar PCB on GJIC, indicating that PC-PLC or sphingomyelinase and Src might be upstream regulators of noncoplanar PCB-induced inhibition of GJIC.},
note = {Place: United States},
keywords = {Animals, Blotting, Cell Line, Epidermal Growth Factor/toxicity, Epithelial Cells/drug effects/enzymology, Gap Junctions/*drug effects/enzymology, Liver/cytology, Mitogen-Activated Protein Kinases/metabolism, Polychlorinated Biphenyls/*toxicity, Rats, Signal Transduction/*drug effects, Sphingomyelin Phosphodiesterase/metabolism, src-Family Kinases/metabolism, Tetradecanoylphorbol Acetate/toxicity, Western},
pubstate = {published},
tppubtype = {article}
}
Polychlorinated biphenyls (PCBs), a structurally diverse group of environmental pollutants, are effective promoters in two-stage cancer models, which implies that epigenetic mechanisms are involved. Inhibition of gap junctional intercellular communication (GJIC) belongs among critical epigenetic events of tumor promotion. We determined the relative potencies of a series of environmentally relevant PCB congeners to inhibit GJIC in vitro in a rat liver epithelial cell line with pluripotent oval cell characteristics. The nonplanar PCBs were potent inhibitors of GJIC, whereas the coplanar PCBs did not inhibit GJIC. We then compared the effects of the coplanar PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the noncoplanar PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) with effects of two model GJIC inhibitors, a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In contrast to TPA or EGF, PCB 153 elicited a long-term downregulation of GJIC (up to 48 h). Using Western blot analysis with phospho-specific antibodies, it was found that PCB 153, and not PCB 126, activated mitogen-activated protein kinases ERK1/2; however in contrast to TPA and EGF, this activation was observed at the time points subsequent to GJIC inhibition. Moreover, blocking of ERK1/2 activation did not prevent the GJIC inhibition induced by PCB 153. Therefore, additional intracellular signaling pathways potentially involved in the downregulation of GJIC by PCBs were screened by using specific chemical probes inhibiting serine/threonine kinases, tyrosine kinases, and phospholipases. The inhibition of diacylglycerol lipase partially blocked and the selective inhibition of Src kinases and phosphatidylcholine-specific phospholipase C (PC-PLC) completely blocked the inhibitory effects of the noncoplanar PCB on GJIC, indicating that PC-PLC or sphingomyelinase and Src might be upstream regulators of noncoplanar PCB-induced inhibition of GJIC.
Nemajerová, Alice; Smarda, Jan; Jurdic, Pierre; Kubala, Lukás; Soucek, Karel; Smardová, Jana
Trichostatin A suppresses transformation by the v-myb oncogene in BM2 cells. Journal Article
In: Journal of hematotherapy & stem cell research, vol. 12, no. 2, pp. 225–235, 2003, ISSN: 1525-8165, (Place: United States).
Abstract | Links | BibTeX | Tags: Acetylation, Animals, Cell Cycle, Cell Differentiation, Cell Line, Cell Transformation, Chickens, Chromatin Assembly and Disassembly/physiology, Genes, Histone Deacetylases/drug effects, Histones/metabolism/physiology, Hydroxamic Acids/*pharmacology, Macrophages/cytology, myb/drug effects/*physiology, Transformed, Viral/*drug effects
@article{nemajerova_trichostatin_2003,
title = {Trichostatin A suppresses transformation by the v-myb oncogene in BM2 cells.},
author = {Alice Nemajerová and Jan Smarda and Pierre Jurdic and Lukás Kubala and Karel Soucek and Jana Smardová},
doi = {10.1089/152581603321628368},
issn = {1525-8165},
year = {2003},
date = {2003-04-01},
journal = {Journal of hematotherapy & stem cell research},
volume = {12},
number = {2},
pages = {225–235},
abstract = {BM2 cells are chicken monoblasts transformed by the v-myb oncogene of avian myeloblastosis virus. The constitutively high v-myb expression interferes with the terminal differentiation of BM2 cells, but these cells can be induced to differentiate into macrophage-like cells by phorbol esters. Histone acetylation plays an important role in regulation of transcription and is particularly relevant to the regulation and pathology of hematopoiesis. In the present study, we examined the contribution of elevated histone acetylation to the differentiation of BM2 cells. Inhibition of the activity of endogenous histone deacetylases by trichostatin A (TSA) resulted in histone hyperacetylation causing cell cycle arrest and differentiation of BM2 cells into macrophage polykaryons. TSA did not affect the level of v-Myb protein in BM2 cells, but it downregulated its transcription activation capability. This suggests that chromatin remodeling can be significantly engaged in regulation of proliferation and differentiation of leukemic cells.},
note = {Place: United States},
keywords = {Acetylation, Animals, Cell Cycle, Cell Differentiation, Cell Line, Cell Transformation, Chickens, Chromatin Assembly and Disassembly/physiology, Genes, Histone Deacetylases/drug effects, Histones/metabolism/physiology, Hydroxamic Acids/*pharmacology, Macrophages/cytology, myb/drug effects/*physiology, Transformed, Viral/*drug effects},
pubstate = {published},
tppubtype = {article}
}
BM2 cells are chicken monoblasts transformed by the v-myb oncogene of avian myeloblastosis virus. The constitutively high v-myb expression interferes with the terminal differentiation of BM2 cells, but these cells can be induced to differentiate into macrophage-like cells by phorbol esters. Histone acetylation plays an important role in regulation of transcription and is particularly relevant to the regulation and pathology of hematopoiesis. In the present study, we examined the contribution of elevated histone acetylation to the differentiation of BM2 cells. Inhibition of the activity of endogenous histone deacetylases by trichostatin A (TSA) resulted in histone hyperacetylation causing cell cycle arrest and differentiation of BM2 cells into macrophage polykaryons. TSA did not affect the level of v-Myb protein in BM2 cells, but it downregulated its transcription activation capability. This suggests that chromatin remodeling can be significantly engaged in regulation of proliferation and differentiation of leukemic cells.
Hoferová, Zuzana; Vacek, Antonín; Hofer, Michal; Macková, Nadezda O.; Soucek, Karel; Egyed, Alena; Fedorocko, Peter
Tumor-host interactions accompanying the growth of the G:5:113 fibrosarcoma in the mouse: possibilities for a new therapeutic approach? Journal Article
In: Cancer investigation, vol. 21, no. 2, pp. 227–236, 2003, ISSN: 0735-7907, (Place: England).
Abstract | Links | BibTeX | Tags: Animals, Cell Count, Cell Cycle/*physiology, Cell Division, Cell Survival/*physiology, Conditioned, Culture Media, Cultured, Fibrosarcoma/blood/*pathology, Granulocytes/pathology, Inbred C3H, Leukocyte Count, Mice, Tumor Cells
@article{hoferova_tumor-host_2003,
title = {Tumor-host interactions accompanying the growth of the G:5:113 fibrosarcoma in the mouse: possibilities for a new therapeutic approach?},
author = {Zuzana Hoferová and Antonín Vacek and Michal Hofer and Nadezda O. Macková and Karel Soucek and Alena Egyed and Peter Fedorocko},
doi = {10.1081/cnv-120016419},
issn = {0735-7907},
year = {2003},
date = {2003-04-01},
journal = {Cancer investigation},
volume = {21},
number = {2},
pages = {227–236},
abstract = {The experiments were aimed at describing in detail some interactions between a solid tumor growing from subcutaneously transplanted G:5:113 fibrosarcoma cells in vivo and its mouse host. The tumor was found to elevate significantly the number of granulocytes in the peripheral blood of the host after having achieved the volume of about 1 cm3 (day 40 after transplantation). Blood plasma from fibrosarcoma-bearing mice stimulated proliferation of progenitor cells for granulocytes and macrophages (GM-CFC) in vitro and suppressed growth of G:5:113 cell population in culture. Interestingly, both effects were observable as early as week 1 when the tumor was still macroscopically invisible and unpalpable. Conditioned medium from cultures of G:5:113 fibrosarcoma cells stimulated proliferation of GM-CFC in vitro. These findings might represent a starting point for studies aimed at designing new therapeutic approaches for the treatment of fibrosarcoma.},
note = {Place: England},
keywords = {Animals, Cell Count, Cell Cycle/*physiology, Cell Division, Cell Survival/*physiology, Conditioned, Culture Media, Cultured, Fibrosarcoma/blood/*pathology, Granulocytes/pathology, Inbred C3H, Leukocyte Count, Mice, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
The experiments were aimed at describing in detail some interactions between a solid tumor growing from subcutaneously transplanted G:5:113 fibrosarcoma cells in vivo and its mouse host. The tumor was found to elevate significantly the number of granulocytes in the peripheral blood of the host after having achieved the volume of about 1 cm3 (day 40 after transplantation). Blood plasma from fibrosarcoma-bearing mice stimulated proliferation of progenitor cells for granulocytes and macrophages (GM-CFC) in vitro and suppressed growth of G:5:113 cell population in culture. Interestingly, both effects were observable as early as week 1 when the tumor was still macroscopically invisible and unpalpable. Conditioned medium from cultures of G:5:113 fibrosarcoma cells stimulated proliferation of GM-CFC in vitro. These findings might represent a starting point for studies aimed at designing new therapeutic approaches for the treatment of fibrosarcoma.
2002
Kubala, Lukás; Cíz, Milan; Vondrácek, Jan; Cerný, Jan; Nemec, Petr; Studeník, Pavel; Cizová, Hana; Lojek, Antonín
In: The Journal of thoracic and cardiovascular surgery, vol. 124, no. 6, pp. 1122–1129, 2002, ISSN: 0022-5223, (Place: United States).
Abstract | Links | BibTeX | Tags: *Cardiac Surgical Procedures, *Heart Transplantation, Cardiopulmonary Bypass, Cytokines/*metabolism, Female, Humans, Interleukin-10/metabolism, Interleukin-6/metabolism, Interleukin-8/metabolism, Male, Middle Aged, Neutrophils/*metabolism, oxidative stress, Phagocytosis, Time Factors
@article{kubala_perioperative_2002,
title = {Perioperative and postoperative course of cytokines and the metabolic activity of neutrophils in human cardiac operations and heart transplantation.},
author = {Lukás Kubala and Milan Cíz and Jan Vondrácek and Jan Cerný and Petr Nemec and Pavel Studeník and Hana Cizová and Antonín Lojek},
doi = {10.1067/mtc.2002.125814},
issn = {0022-5223},
year = {2002},
date = {2002-12-01},
journal = {The Journal of thoracic and cardiovascular surgery},
volume = {124},
number = {6},
pages = {1122–1129},
abstract = {OBJECTIVES: The purpose of this study was to compare systemic inflammatory responses after heart transplantation and nontransplant cardiac operations, both involving cardiopulmonary bypass with a focus on the role of polymorphonuclear leukocytes. METHODS: Lipid peroxidation, blood phagocyte radical production, and interleukin 6, 8, and 10 plasma concentrations during surgical intervention and on the first and seventh postoperative days were evaluated in patients undergoing heart transplantation (n = 24) and in patients not undergoing transplantation (n = 30). RESULTS: Levels of interleukin 6, 8, and 10 increased in both groups of patients during early reperfusion. They normalized within the first postoperative day in the transplant group, whereas the nontransplant group's interleukin 6 and 8 levels remained increased on the seventh day after the operation. Interleukin 10 plasma levels were higher in the heart transplant group during reperfusion. Lipid peroxidation was increased after the operation in both groups of patients. Phagocyte activity was enhanced at reperfusion and at all other sampling times only in the nontransplant group. On the other hand, phagocyte activity oscillated around the preoperative level during heart transplantation, or it was even decreased. CONCLUSION: Both cardiac operations involving heart transplantation and those without transplantation are associated with increased oxidative stress and an enhanced production of proinflammatory and anti-inflammatory cytokines. Differences in interleukin 10 production and phagocyte activity could be caused mainly by the immunosuppressive therapy in heart transplant operations.},
note = {Place: United States},
keywords = {*Cardiac Surgical Procedures, *Heart Transplantation, Cardiopulmonary Bypass, Cytokines/*metabolism, Female, Humans, Interleukin-10/metabolism, Interleukin-6/metabolism, Interleukin-8/metabolism, Male, Middle Aged, Neutrophils/*metabolism, oxidative stress, Phagocytosis, Time Factors},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVES: The purpose of this study was to compare systemic inflammatory responses after heart transplantation and nontransplant cardiac operations, both involving cardiopulmonary bypass with a focus on the role of polymorphonuclear leukocytes. METHODS: Lipid peroxidation, blood phagocyte radical production, and interleukin 6, 8, and 10 plasma concentrations during surgical intervention and on the first and seventh postoperative days were evaluated in patients undergoing heart transplantation (n = 24) and in patients not undergoing transplantation (n = 30). RESULTS: Levels of interleukin 6, 8, and 10 increased in both groups of patients during early reperfusion. They normalized within the first postoperative day in the transplant group, whereas the nontransplant group's interleukin 6 and 8 levels remained increased on the seventh day after the operation. Interleukin 10 plasma levels were higher in the heart transplant group during reperfusion. Lipid peroxidation was increased after the operation in both groups of patients. Phagocyte activity was enhanced at reperfusion and at all other sampling times only in the nontransplant group. On the other hand, phagocyte activity oscillated around the preoperative level during heart transplantation, or it was even decreased. CONCLUSION: Both cardiac operations involving heart transplantation and those without transplantation are associated with increased oxidative stress and an enhanced production of proinflammatory and anti-inflammatory cytokines. Differences in interleukin 10 production and phagocyte activity could be caused mainly by the immunosuppressive therapy in heart transplant operations.
Vondrácek, Jan; Kozubík, Alois; Machala, Miroslav
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 70, no. 2, pp. 193–201, 2002, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Breast Neoplasms/*metabolism, Cell Cycle/*drug effects/genetics, Cell Cycle/drug effects/genetics, Cultured, Estrogen Receptor alpha, Estrogen Receptor Modulators/pharmacology, Estrogen/genetics/*metabolism, G1 Phase/drug effects/genetics, Genes, Genetic/drug effects, Humans, Phosphorylation/drug effects, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter/*genetics, Resting Phase, S Phase/drug effects/genetics, Transcription, Tumor Cells
@article{vondracek_modulation_2002,
title = {Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.},
author = {Jan Vondrácek and Alois Kozubík and Miroslav Machala},
doi = {10.1093/toxsci/70.2.193},
issn = {1096-6080 1096-0929},
year = {2002},
date = {2002-12-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {70},
number = {2},
pages = {193–201},
abstract = {It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.},
note = {Place: United States},
keywords = {Breast Neoplasms/*metabolism, Cell Cycle/*drug effects/genetics, Cell Cycle/drug effects/genetics, Cultured, Estrogen Receptor alpha, Estrogen Receptor Modulators/pharmacology, Estrogen/genetics/*metabolism, G1 Phase/drug effects/genetics, Genes, Genetic/drug effects, Humans, Phosphorylation/drug effects, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter/*genetics, Resting Phase, S Phase/drug effects/genetics, Transcription, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.
Vaculová, Alena; Hofmanova, Jirina; Soucek, Karel; Kovariková, Martina; Kozubík, Alois
Tumor necrosis factor-alpha induces apoptosis associated with poly(ADP-ribose) polymerase cleavage in HT-29 colon cancer cells. Journal Article
In: Anticancer research, vol. 22, no. 3, pp. 1635–1639, 2002, ISSN: 0250-7005, (Place: Greece).
Abstract | BibTeX | Tags: Apoptosis/*drug effects, Caspase 3, Caspases/metabolism, Cell Death/drug effects, Cell Division/drug effects, HT29 Cells/*drug effects/enzymology/pathology, Humans, Kinetics, Poly(ADP-ribose) Polymerases/*metabolism, Reactive Oxygen Species/metabolism, Tumor Necrosis Factor-alpha/*pharmacology
@article{vaculova_tumor_2002,
title = {Tumor necrosis factor-alpha induces apoptosis associated with poly(ADP-ribose) polymerase cleavage in HT-29 colon cancer cells.},
author = {Alena Vaculová and Jirina Hofmanova and Karel Soucek and Martina Kovariková and Alois Kozubík},
issn = {0250-7005},
year = {2002},
date = {2002-06-01},
journal = {Anticancer research},
volume = {22},
number = {3},
pages = {1635–1639},
abstract = {BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known for its selective cytotoxic activity on tumour cells. We analysed the response of HT-29 human colon carcinoma cells to this cytokine. MATERIALS AND METHODS: After TNF-alpha treatment, cell proliferation, cell cycle, reactive oxygen species (ROS) production (flow cytometry), the amount of apoptotic cells (flow cytometry, fluorescence microscopy), cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 activity (Western blotting) were detected. RESULTS: TNF-alpha induced a decrease of cell growth and viability, an accumulation of cells in the S-phase of the cell cycle, an increase of subdiploid cell population and nuclear chromatin condensation and fragmentation, but not sooner than 96-120 hours. However, earlier events characteristic of apoptosis occurred, such as caspase-3 activation, PARP cleavage to 89 kDa fragment and changes in ROS production. CONCLUSION: We demonstrated that, in addition to being an early marker of apoptosis, activation of caspase-3 and degradation of PARP may play a causative role in HT-29 cell death induced by TNF-alpha.},
note = {Place: Greece},
keywords = {Apoptosis/*drug effects, Caspase 3, Caspases/metabolism, Cell Death/drug effects, Cell Division/drug effects, HT29 Cells/*drug effects/enzymology/pathology, Humans, Kinetics, Poly(ADP-ribose) Polymerases/*metabolism, Reactive Oxygen Species/metabolism, Tumor Necrosis Factor-alpha/*pharmacology},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known for its selective cytotoxic activity on tumour cells. We analysed the response of HT-29 human colon carcinoma cells to this cytokine. MATERIALS AND METHODS: After TNF-alpha treatment, cell proliferation, cell cycle, reactive oxygen species (ROS) production (flow cytometry), the amount of apoptotic cells (flow cytometry, fluorescence microscopy), cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 activity (Western blotting) were detected. RESULTS: TNF-alpha induced a decrease of cell growth and viability, an accumulation of cells in the S-phase of the cell cycle, an increase of subdiploid cell population and nuclear chromatin condensation and fragmentation, but not sooner than 96-120 hours. However, earlier events characteristic of apoptosis occurred, such as caspase-3 activation, PARP cleavage to 89 kDa fragment and changes in ROS production. CONCLUSION: We demonstrated that, in addition to being an early marker of apoptosis, activation of caspase-3 and degradation of PARP may play a causative role in HT-29 cell death induced by TNF-alpha.
Pacherník, Jirí; Hampl, Ales; Soucek, Karel; Kovaríková, Martina; Andrysík, Zdenek; Hofmanová, Jirina; Kozubík, Alois
Multiple biological effects of inhibitors of arachidonic acid metabolism on human keratinocytes. Journal Article
In: Archives of dermatological research, vol. 293, no. 12, pp. 626–633, 2002, ISSN: 0340-3696, (Place: Germany).
Abstract | Links | BibTeX | Tags: 11, 14-Eicosatetraynoic Acid/pharmacology, 5, 8, Arachidonic Acid/*antagonists & inhibitors, Cell Differentiation/drug effects, Cell Division/drug effects, Cell Line, Cell Survival/drug effects, Cyclooxygenase Inhibitors/pharmacology, Humans, Indoles/pharmacology, Keratinocytes/cytology/*drug effects/*physiology, Lipoxygenase Inhibitors/pharmacology, Transformed, Umbelliferones/pharmacology
@article{pachernik_multiple_2002,
title = {Multiple biological effects of inhibitors of arachidonic acid metabolism on human keratinocytes.},
author = {Jirí Pacherník and Ales Hampl and Karel Soucek and Martina Kovaríková and Zdenek Andrysík and Jirina Hofmanová and Alois Kozubík},
doi = {10.1007/s00403-001-0288-5},
issn = {0340-3696},
year = {2002},
date = {2002-02-01},
journal = {Archives of dermatological research},
volume = {293},
number = {12},
pages = {626–633},
abstract = {BACKGROUND: Various compounds that inhibit processing of arachidonic acid (AA) are being intensively tested for their antitumour activity. However, the mechanisms responsible for such activity remain rather elusive. To approach this issue, we examined the effects of several structurally different inhibitors of AA metabolism in the human keratinocyte HaCaT cell line. METHODS: Several parameters were determined in HaCaT cells exposed to increasing concentrations of the inhibitors for 24 and/or 48 h. These included (1) oxidoreductase activity, total protein mass and cell cycle distribution to assess cell proliferation, (2) degradation of PARP protein to assess apoptosis, and (3) cell morphology, distribution of F-actin and expression of cytokeratins and E-cadherin to evaluate changes in differentiation status. RESULTS: While eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), esculetin and MK-886 reduced proliferation of HaCaT cells, the cyclooxygenase inhibitors indomethacin and piroxicam had no such effects. Esculetin and NDGA arrested cells in S phase, and ETYA and MK-886 delayed cell progression through G(1) phase. Higher concentrations of NDGA, MK886 and/or ETYA caused cleavage of PARP. No changes in the expression of cytokeratins and E-cadherin were observed upon treatment with any of the inhibitors. However, esculetin induced redistribution of F-actin accompanied by increased cell adhesion and size. CONCLUSION: Our findings indicate that, in addition to their ability to inhibit cell proliferation and to induce apoptosis, lipoxygenase inhibitors and/or ETYA may also elicit other important physiological responses in HaCaT keratinocytes.},
note = {Place: Germany},
keywords = {11, 14-Eicosatetraynoic Acid/pharmacology, 5, 8, Arachidonic Acid/*antagonists & inhibitors, Cell Differentiation/drug effects, Cell Division/drug effects, Cell Line, Cell Survival/drug effects, Cyclooxygenase Inhibitors/pharmacology, Humans, Indoles/pharmacology, Keratinocytes/cytology/*drug effects/*physiology, Lipoxygenase Inhibitors/pharmacology, Transformed, Umbelliferones/pharmacology},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Various compounds that inhibit processing of arachidonic acid (AA) are being intensively tested for their antitumour activity. However, the mechanisms responsible for such activity remain rather elusive. To approach this issue, we examined the effects of several structurally different inhibitors of AA metabolism in the human keratinocyte HaCaT cell line. METHODS: Several parameters were determined in HaCaT cells exposed to increasing concentrations of the inhibitors for 24 and/or 48 h. These included (1) oxidoreductase activity, total protein mass and cell cycle distribution to assess cell proliferation, (2) degradation of PARP protein to assess apoptosis, and (3) cell morphology, distribution of F-actin and expression of cytokeratins and E-cadherin to evaluate changes in differentiation status. RESULTS: While eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), esculetin and MK-886 reduced proliferation of HaCaT cells, the cyclooxygenase inhibitors indomethacin and piroxicam had no such effects. Esculetin and NDGA arrested cells in S phase, and ETYA and MK-886 delayed cell progression through G(1) phase. Higher concentrations of NDGA, MK886 and/or ETYA caused cleavage of PARP. No changes in the expression of cytokeratins and E-cadherin were observed upon treatment with any of the inhibitors. However, esculetin induced redistribution of F-actin accompanied by increased cell adhesion and size. CONCLUSION: Our findings indicate that, in addition to their ability to inhibit cell proliferation and to induce apoptosis, lipoxygenase inhibitors and/or ETYA may also elicit other important physiological responses in HaCaT keratinocytes.
Hoferová, Zuzana; Fedorocko, Peter; Hofmanová, Jirina; Hofer, Michal; Znojil, Vladimír; Minksová, Katerina; Soucek, Karel; Egyed, Alena; Kozubík, Alois
The effect of nonsteroidal antiinflammatory drugs ibuprofen, flurbiprofen, and diclofenac on in vitro and in vivo growth of mouse fibrosarcoma. Journal Article
In: Cancer investigation, vol. 20, no. 4, pp. 490–498, 2002, ISSN: 0735-7907, (Place: England).
Abstract | Links | BibTeX | Tags: Animals, Anti-Inflammatory Agents, Cell Cycle/drug effects, Cell Division/drug effects, Cultured/*drug effects, Diclofenac/*therapeutic use, Experimental, Fibrosarcoma/*drug therapy/pathology, Flurbiprofen/*therapeutic use, Ibuprofen/*therapeutic use, In Vitro Techniques, Inbred C3H, Male, Mice, Neoplasms, Non-Steroidal/*therapeutic use, Survival Rate, Tumor Cells
@article{hoferova_effect_2002,
title = {The effect of nonsteroidal antiinflammatory drugs ibuprofen, flurbiprofen, and diclofenac on in vitro and in vivo growth of mouse fibrosarcoma.},
author = {Zuzana Hoferová and Peter Fedorocko and Jirina Hofmanová and Michal Hofer and Vladimír Znojil and Katerina Minksová and Karel Soucek and Alena Egyed and Alois Kozubík},
doi = {10.1081/cnv-120002149},
issn = {0735-7907},
year = {2002},
date = {2002-01-01},
journal = {Cancer investigation},
volume = {20},
number = {4},
pages = {490–498},
abstract = {For suppression of primary G:5:113 fibrosarcoma growth, three structurally different cyclooxygenase (COX) inhibitors (ibuprofen, flurbiprofen, and diclofenac) were administered intraperitoneally (i.p.) in two regimens starting on day 5 after tumor-cell inoculation. Repeated application of 0.15 mg/mouse/day during 14 consecutive days significantly suppressed the tumor growth and increased the percentage of surviving mice. Similar tendency, however without significant differences, was observed when animals were given 0.5 mg/day for five consecutive days. These results suggest that a time schedule of drug application is important for the therapeutic effect. Suppressive effect of diclofenac and flurbiprofen on tumor growth was also observed under in vitro conditions. We conclude that suppressive effect of these drugs on tumor growth in vivo comprises both direct effects of COX inhibitors on fibrosarcoma cells and indirect effects that are presumably mediated by extratumoral sources. Our findings encourage the use of COX inhibitors in the therapy of fibrosarcoma.},
note = {Place: England},
keywords = {Animals, Anti-Inflammatory Agents, Cell Cycle/drug effects, Cell Division/drug effects, Cultured/*drug effects, Diclofenac/*therapeutic use, Experimental, Fibrosarcoma/*drug therapy/pathology, Flurbiprofen/*therapeutic use, Ibuprofen/*therapeutic use, In Vitro Techniques, Inbred C3H, Male, Mice, Neoplasms, Non-Steroidal/*therapeutic use, Survival Rate, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
For suppression of primary G:5:113 fibrosarcoma growth, three structurally different cyclooxygenase (COX) inhibitors (ibuprofen, flurbiprofen, and diclofenac) were administered intraperitoneally (i.p.) in two regimens starting on day 5 after tumor-cell inoculation. Repeated application of 0.15 mg/mouse/day during 14 consecutive days significantly suppressed the tumor growth and increased the percentage of surviving mice. Similar tendency, however without significant differences, was observed when animals were given 0.5 mg/day for five consecutive days. These results suggest that a time schedule of drug application is important for the therapeutic effect. Suppressive effect of diclofenac and flurbiprofen on tumor growth was also observed under in vitro conditions. We conclude that suppressive effect of these drugs on tumor growth in vivo comprises both direct effects of COX inhibitors on fibrosarcoma cells and indirect effects that are presumably mediated by extratumoral sources. Our findings encourage the use of COX inhibitors in the therapy of fibrosarcoma.
Bláha, Ludek; Kapplová, Petra; Vondrácek, Jan; Upham, Brad; Machala, Miroslav
Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons. Journal Article
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 65, no. 1, pp. 43–51, 2002, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Carcinogens/toxicity, Cell Communication/*drug effects, Cell Line, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Epithelium/drug effects, Gap Junctions/*drug effects, Liver/cytology/drug effects, Molecular Structure, Polycyclic Aromatic Hydrocarbons/chemistry/*toxicity, Rats, Tetradecanoylphorbol Acetate/toxicity, United States, United States Environmental Protection Agency/standards
@article{blaha_inhibition_2002,
title = {Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons.},
author = {Ludek Bláha and Petra Kapplová and Jan Vondrácek and Brad Upham and Miroslav Machala},
doi = {10.1093/toxsci/65.1.43},
issn = {1096-6080 1096-0929},
year = {2002},
date = {2002-01-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {65},
number = {1},
pages = {43–51},
abstract = {Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although microM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50-75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.},
note = {Place: United States},
keywords = {Animals, Carcinogens/toxicity, Cell Communication/*drug effects, Cell Line, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Epithelium/drug effects, Gap Junctions/*drug effects, Liver/cytology/drug effects, Molecular Structure, Polycyclic Aromatic Hydrocarbons/chemistry/*toxicity, Rats, Tetradecanoylphorbol Acetate/toxicity, United States, United States Environmental Protection Agency/standards},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs) are a broad class of ubiquitous environmental pollutants with known or suspected carcinogenic properties. Tumor promotion is a cell-proliferative step of cancer that requires the removal of cells from growth suppression via the inhibition of gap-junctional intercellular communication (GJIC). Inhibition of GJIC measured with an in vitro WB-F344 rat liver epithelial cell system was used to assess the relative potencies of 13 PAHs suggested by the U.S. Environmental Protection Agency (EPA) as the principal contaminants and 22 other PAHs, most of them identified in environmental samples. Maximal inhibition of GJIC was detected after 30 min of exposure, followed by a recovery in intercellular communication after an additional 30 min of exposure, suggesting a transient character of inhibition. Although microM concentrations of PAHs were required to reach the inhibition level equal to the model tumor promoter phorbol 12-myristate 13-acetate (IC50 = 8 nM), 12 of the PAHs under study were found to be strong inhibitors of GJIC (strongest effects were observed with fluoranthene, picene, 5-methylchrysene and nine additional PAHs). The other nine PAHs, including benzo[a]pyrene, inhibited GJIC only up to 50-75% of the control level. Interestingly, several high molecular weight PAHs with known strong carcinogenic properties possessed only weak (dibenzopyrenes) or no inhibition potency (dibenzofluoranthenes, naphtho[2,3-a]pyrene and benzo[a]perylene). Based on the IC50 values related to the reference PAH benzo[a]pyrene, we suggested arbitrary values of inhibition equivalency factors (GJIC-IEFs) ranging from 0 (noninhibiting PAHs) to 10.0 (strongest inhibitors), suitable for the purposes of environmental risk assessment.