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Decytabine enhances cytotoxicity induced by oxaliplatin and 5-fluorouracil in the colorectal cancer cell line Colo-205.

Flis S, Gnyszka A, Misiewicz-Krzemińska I, Spławiński J - Cancer Cell Int. (2009)

Bottom Line: To test this we have addressed the hypothesis that DNA methyltransferase inhibitors (DNMTi), decytabine and zebularine, potentiate inhibitory effects of classical anti-CRC cytostatics, oxaliplatin and 5-fluorouracil (5-FU), on survival of CRC cells in vitro.Isobole and median effect analysis revealed that decytabine shows potent synergistic interaction with oxaliplatin and 5-FU and that this is probably not the class effect of DNMTi as zebularine shows strong antagonistic interaction with oxaliplatin.The observed synergism between decytabine and cytostatics is most probably related to the augmented apoptotic signal and allowed for significant (both biologically and statistically) reduction of the cytotoxic doses of cytostatics used.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, National Medicines Institute, Warsaw, Poland. sylwia.flis@yahoo.pl

ABSTRACT

Background: DNA methylation is an epigenetic phenomenon known to play an important role in the development of cancers, including colorectal cancer (CRC). Aberrant methylation of promoter regions of genes is potentially reversible, and if methylation is important for cancer survival, demethylation should do the opposite. To test this we have addressed the hypothesis that DNA methyltransferase inhibitors (DNMTi), decytabine and zebularine, potentiate inhibitory effects of classical anti-CRC cytostatics, oxaliplatin and 5-fluorouracil (5-FU), on survival of CRC cells in vitro.

Results: Isobole and median effect analysis revealed that decytabine shows potent synergistic interaction with oxaliplatin and 5-FU and that this is probably not the class effect of DNMTi as zebularine shows strong antagonistic interaction with oxaliplatin. The synergistic combination treatment was also applied to the cultures to investigate their mechanisms of action. We have shown that combinations of decytabine with cytostatics produced dose-dependent growth inhibition and treatment-induced apoptosis.

Conclusion: The observed synergism between decytabine and cytostatics is most probably related to the augmented apoptotic signal and allowed for significant (both biologically and statistically) reduction of the cytotoxic doses of cytostatics used.

No MeSH data available.


Related in: MedlinePlus

Effect of cytostatics and DNMTi agents combinations on induction of apoptosis. Percentage of apoptosis determined by FACS analysis, after 72 h treatment with demethylating agents, cytostatics and their combinations in concentrations as indicated. Each column represented of four independent experiments. The results are expressed as the mean ± SD. Induction of apoptosis by cytostatics and demethylating agents was significant in comparison with control; astericks denote p < 0.05 for combination of cytostatics and demethylating agents versus cytostatics alone.
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Figure 5: Effect of cytostatics and DNMTi agents combinations on induction of apoptosis. Percentage of apoptosis determined by FACS analysis, after 72 h treatment with demethylating agents, cytostatics and their combinations in concentrations as indicated. Each column represented of four independent experiments. The results are expressed as the mean ± SD. Induction of apoptosis by cytostatics and demethylating agents was significant in comparison with control; astericks denote p < 0.05 for combination of cytostatics and demethylating agents versus cytostatics alone.

Mentions: Treatment of CRC cells with oxaliplatin or 5-FU alone induced apoptosis in ~40% of the cells. The percentage of apoptotic cells increased when cells were coincubated with decytabine: to 60% in the case of oxaliplatin and to ~55% in the case of 5-FU (Fig. 5). Combination of zebularine with oxaliplatine did not increase apoptosis whereas combination with 5-FU increased significantly the number of apoptotic CRC cells.


Decytabine enhances cytotoxicity induced by oxaliplatin and 5-fluorouracil in the colorectal cancer cell line Colo-205.

Flis S, Gnyszka A, Misiewicz-Krzemińska I, Spławiński J - Cancer Cell Int. (2009)

Effect of cytostatics and DNMTi agents combinations on induction of apoptosis. Percentage of apoptosis determined by FACS analysis, after 72 h treatment with demethylating agents, cytostatics and their combinations in concentrations as indicated. Each column represented of four independent experiments. The results are expressed as the mean ± SD. Induction of apoptosis by cytostatics and demethylating agents was significant in comparison with control; astericks denote p < 0.05 for combination of cytostatics and demethylating agents versus cytostatics alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683807&req=5

Figure 5: Effect of cytostatics and DNMTi agents combinations on induction of apoptosis. Percentage of apoptosis determined by FACS analysis, after 72 h treatment with demethylating agents, cytostatics and their combinations in concentrations as indicated. Each column represented of four independent experiments. The results are expressed as the mean ± SD. Induction of apoptosis by cytostatics and demethylating agents was significant in comparison with control; astericks denote p < 0.05 for combination of cytostatics and demethylating agents versus cytostatics alone.
Mentions: Treatment of CRC cells with oxaliplatin or 5-FU alone induced apoptosis in ~40% of the cells. The percentage of apoptotic cells increased when cells were coincubated with decytabine: to 60% in the case of oxaliplatin and to ~55% in the case of 5-FU (Fig. 5). Combination of zebularine with oxaliplatine did not increase apoptosis whereas combination with 5-FU increased significantly the number of apoptotic CRC cells.

Bottom Line: To test this we have addressed the hypothesis that DNA methyltransferase inhibitors (DNMTi), decytabine and zebularine, potentiate inhibitory effects of classical anti-CRC cytostatics, oxaliplatin and 5-fluorouracil (5-FU), on survival of CRC cells in vitro.Isobole and median effect analysis revealed that decytabine shows potent synergistic interaction with oxaliplatin and 5-FU and that this is probably not the class effect of DNMTi as zebularine shows strong antagonistic interaction with oxaliplatin.The observed synergism between decytabine and cytostatics is most probably related to the augmented apoptotic signal and allowed for significant (both biologically and statistically) reduction of the cytotoxic doses of cytostatics used.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, National Medicines Institute, Warsaw, Poland. sylwia.flis@yahoo.pl

ABSTRACT

Background: DNA methylation is an epigenetic phenomenon known to play an important role in the development of cancers, including colorectal cancer (CRC). Aberrant methylation of promoter regions of genes is potentially reversible, and if methylation is important for cancer survival, demethylation should do the opposite. To test this we have addressed the hypothesis that DNA methyltransferase inhibitors (DNMTi), decytabine and zebularine, potentiate inhibitory effects of classical anti-CRC cytostatics, oxaliplatin and 5-fluorouracil (5-FU), on survival of CRC cells in vitro.

Results: Isobole and median effect analysis revealed that decytabine shows potent synergistic interaction with oxaliplatin and 5-FU and that this is probably not the class effect of DNMTi as zebularine shows strong antagonistic interaction with oxaliplatin. The synergistic combination treatment was also applied to the cultures to investigate their mechanisms of action. We have shown that combinations of decytabine with cytostatics produced dose-dependent growth inhibition and treatment-induced apoptosis.

Conclusion: The observed synergism between decytabine and cytostatics is most probably related to the augmented apoptotic signal and allowed for significant (both biologically and statistically) reduction of the cytotoxic doses of cytostatics used.

No MeSH data available.


Related in: MedlinePlus