2009
Lincová, Eva; Hampl, Ales; Pernicová, Zuzana; Starsíchová, Andrea; Krcmár, Pavel; Machala, Miroslav; Kozubík, Alois; Soucek, Karel
In: Biochemical pharmacology, vol. 78, no. 6, pp. 561–572, 2009, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: Anti-Inflammatory Agents, Antineoplastic Agents/pharmacology, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/physiology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21/*biosynthesis, Enzyme Induction, Epithelial Cells/*drug effects/pathology, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Growth Differentiation Factor 15/biosynthesis, Humans, Indomethacin/pharmacology, Male, Non-Steroidal/*pharmacology, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms/*pathology, Proto-Oncogene Proteins c-akt/*metabolism, RNA Interference, Signal Transduction/drug effects/physiology, Tumor, Tumor Suppressor Protein p53/genetics/*metabolism
@article{lincova_multiple_2009,
title = {Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs.},
author = {Eva Lincová and Ales Hampl and Zuzana Pernicová and Andrea Starsíchová and Pavel Krcmár and Miroslav Machala and Alois Kozubík and Karel Soucek},
doi = {10.1016/j.bcp.2009.05.001},
issn = {1873-2968 0006-2952},
year = {2009},
date = {2009-09-01},
journal = {Biochemical pharmacology},
volume = {78},
number = {6},
pages = {561–572},
abstract = {Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.},
note = {Place: England},
keywords = {Anti-Inflammatory Agents, Antineoplastic Agents/pharmacology, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/physiology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21/*biosynthesis, Enzyme Induction, Epithelial Cells/*drug effects/pathology, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Growth Differentiation Factor 15/biosynthesis, Humans, Indomethacin/pharmacology, Male, Non-Steroidal/*pharmacology, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms/*pathology, Proto-Oncogene Proteins c-akt/*metabolism, RNA Interference, Signal Transduction/drug effects/physiology, Tumor, Tumor Suppressor Protein p53/genetics/*metabolism},
pubstate = {published},
tppubtype = {article}
}
Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.
2002
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.