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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 combination treatment with cytostatics and DNMTi agents on survival of the Colo-205 cells. Human colorectal cancer cells were exposed to 5-fluorouracil (5-FU) (A) or oxaliplatin (B) with and without demethylating agents, decytabine and zebularine (concentrations, in μM, below figures) for 72 h. Each bar represents the mean ± SD (n = 5), asterisks indicates significance at p < 0.05, for comparison with 5-FU or oxaliplatin.
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Figure 1: Effect of combination treatment with cytostatics and DNMTi agents on survival of the Colo-205 cells. Human colorectal cancer cells were exposed to 5-fluorouracil (5-FU) (A) or oxaliplatin (B) with and without demethylating agents, decytabine and zebularine (concentrations, in μM, below figures) for 72 h. Each bar represents the mean ± SD (n = 5), asterisks indicates significance at p < 0.05, for comparison with 5-FU or oxaliplatin.

Mentions: The studied drugs, used in the concentration range from 3.75 to 100 μM, inhibited the survival of Colo-205 cells in vitro. Among tested compounds that were incubated with Colo-205 cells for 48 and 72 hours oxaliplatin and 5-FU showed the most potent inhibition of Colo-205 cells growth with the maximum following 72 hours incubation time (Fig. 1). The inhibitory effects of cytostatics were dose dependent and the correlation coefficients (estimated from the inhibitory dose-response curves) were above 0.9. Demethylating agents, decytabine and zebularine, have demonstrated different mode of inhibition: decytabine was already inhibitory at low concentrations (starting from 7.5 μM), whereas zebularine showed non-significant stimulation of Colo-205 cells growth at low concentration and was inhibitory, starting from concentrations of 45 μM.


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 combination treatment with cytostatics and DNMTi agents on survival of the Colo-205 cells. Human colorectal cancer cells were exposed to 5-fluorouracil (5-FU) (A) or oxaliplatin (B) with and without demethylating agents, decytabine and zebularine (concentrations, in μM, below figures) for 72 h. Each bar represents the mean ± SD (n = 5), asterisks indicates significance at p < 0.05, for comparison with 5-FU or oxaliplatin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Effect of combination treatment with cytostatics and DNMTi agents on survival of the Colo-205 cells. Human colorectal cancer cells were exposed to 5-fluorouracil (5-FU) (A) or oxaliplatin (B) with and without demethylating agents, decytabine and zebularine (concentrations, in μM, below figures) for 72 h. Each bar represents the mean ± SD (n = 5), asterisks indicates significance at p < 0.05, for comparison with 5-FU or oxaliplatin.
Mentions: The studied drugs, used in the concentration range from 3.75 to 100 μM, inhibited the survival of Colo-205 cells in vitro. Among tested compounds that were incubated with Colo-205 cells for 48 and 72 hours oxaliplatin and 5-FU showed the most potent inhibition of Colo-205 cells growth with the maximum following 72 hours incubation time (Fig. 1). The inhibitory effects of cytostatics were dose dependent and the correlation coefficients (estimated from the inhibitory dose-response curves) were above 0.9. Demethylating agents, decytabine and zebularine, have demonstrated different mode of inhibition: decytabine was already inhibitory at low concentrations (starting from 7.5 μM), whereas zebularine showed non-significant stimulation of Colo-205 cells growth at low concentration and was inhibitory, starting from concentrations of 45 μM.

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