DNA methylation is an epigenetic phenomenon known to play an important role in the development and progression of human cancer. Enzyme responsible for this process is DNA methyltransferase 1 (DNMT1) ...that maintains an altered methylation pattern by copying it from parent to daughter DNA strands after replication. Aberrant methylation of the promoter regions of genes critical for normal cellular functions is potentially reversible. Therefore, inactivation of DNMT1 seems to be a valuable target for the development of cancer therapies. Currently, the most popular DNMT inhibitors (DNMTi) are cytidine analogues like 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine) and pyrimidin-2-one ribonucleoside (zebularine). In colorectal cancer, epigenetic modifications play an essential role at each step of carcinogenesis. Therefore, we have addressed the hypothesis that DNA methyltransferase inhibitors may potentiate inhibitory effects of classical chemotherapeutic agents, such as oxaliplatin and 5-fluorouracil (5-FU), commonly used in colorectal cancer therapy. Here, our report shows that DNMTi can have positive interactions with standard chemotherapeutics in colorectal cancer treatment. Using pharmacological models for the drug-drug interaction analysis, we have revealed that the combination of decitabine with 5-FU or oxaliplatin shows the most attractive interaction (synergism), whereas the effect of zebularine in combinations with chemotherapeutics is moderate and may be depended on genetic/epigenetic background of a cell line or secondary drug used in combination. Our results suggest that DNMTi administered in combination with standard chemotherapeutics might improve the treatment of patients with colorectal cancers.
Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups, stimulating chromatin condensation, and promoting ...transcriptional repression. Since aberrant epigenetic changes are a hallmark of cancer, HDACs appear a promising target for pharmacological inhibition. To test this we have addressed the hypothesis that histone deacetylase inhibitors (HDACi), MS275 and SBHA, potentiate inhibitory effects of classical anti-colorectal cancer cytostatic, oxaliplatin, on survival of colorectal cancer (CRC) cells
in vitro. We are reporting here that HDACi shows potent synergistic interaction with oxaliplatin. The observed synergism between HDACi and oxaliplatin is most probably related to the augmented apoptotic signal and allowed for significant reduction of doses of anticancer agents used.
Histone deacetylases (HDACs) activity determines the acetylation status of histons, and has the ability to regulate gene expression through chromatin remodelling. HDACs are a promising target for ...pharmacological inhibition, since it has been discovered that some genes are repressed by their inappropriate recruitment. To test this we have addressed the hypothesis that histone deacetylase inhibitors SBHA and MS275 potentiate inhibitory effects of classical anti-colorectal cancer cytostatic, 5-fluorouracil (5-FU), on survival of colorectal cancer (CRC) cells
in vitro. We are reporting here that HDAC inhibitors show potent synergistic interaction with 5-FU. The observed synergism between HDAC inhibitors and 5-FU is most probably related to the augmented apoptotic signal allowed for significant (both biological and statistical) reduction of the cytotoxic doses.
The DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are the most successful epigenetic drugs to date and are still the most widely used as epigenetic modulators, even though their ...application for oncological diseases is restricted by their relative toxicity and poor chemical stability. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one), a more stable and less toxic cytidine analog, is another inhibitor of DNMT with concomitant inhibitory activity towards cytidine deaminase. Unfortunately, there is no new information related to the possible clinical applications of zebularine. Although many new inhibitors of DNMT have been identified, none of them can so far replace azacytidine, decitabine and, to a lesser degree, zebularine. This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy. We also discuss the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles, reflecting their complex and partially overlapping biological effects.
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.
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.
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.
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•Gradient copolymers of 2-propyl-2-oxazine and 2-methyl-2-oxazoline.•Controlled full acidic hydrolysis of poly(cyclic iminoethers) leads to polyamines.•Adjacent r.u. has a critical ...influence on copolymer hydrolytic rates.•Antimicrobial activity of L-PTMI-co-L-PEI copolymers increases with L-PTMI content.•No decrease in activity when up to 40% of r.u. of PrOzi is introduced to L-PTMI.
Polymeric antimicrobial agents are intensively investigated as potential novel antibiotics. In this work we use copolymerization of 2-propyl-2-oxazine (PrOzi) and 2-methyl-2-oxazoline (MeOx) combined with hydrolysis of the polymer side chains as a tool to obtain various linear polymeric derivatives of polytrimethylenimines (L-PTMI) and polyethylenimine (L-PEI). To obtain well-defined polymers, initially we determined copolymerization rates, and subsequently, we investigated the hydrolytic rates of various repeating units, namely PrOzi, MeOx, and 2-methyl-2-oxazine (MeOzi) in both homo- and copolymers. We observed that the structure of the polymeric main chain significantly influences the rate of acidic hydrolysis. In particular, the protonated L–PEI repeating unit (r.u.) accelerates the hydrolytic cleavage of the amide bond more than the protonated L-PTMI r.u., due to the shorter distance between amine centers.
The biological activity of the polymers was assessed against three model microorganisms, namely Escherichia coli, Staphylococcus aureus and Candida albicans, and benchmarked in toxicity test against human lung fibroblast cell line. The antibacterial activity of L-PTMI-co-L–PEI increases monotonically with the increasing content of PTMI r.u., indicating an additive effect of covalently bonded L-PTMI and L-PEI. The antimicrobial activity of the copolymers is almost identical to that of the tested polymer blends in the corresponding ratios.
The introduction of up to 40 % of PrOzi r.u. into the polyamine structure of PTMI (PPrOzi–co-L-PTMI copolymer) does not decrease the antimicrobial activity, compared to L–PTMI. The molecule remains active, particularly against Staphylococcus aureus (MIC = 4 μg/mL). At the same time, the presence of amide r.u. reduces toxicity. The highest observable selectivity index can reach values as high as 20 (PPrOzi40%–co-L-PTMI60%).
DNA methylation is an epigenetic phenomenon known to play an important role in the development and progression of human cancer. Enzyme responsible for this process is DNA methyltransferase 1 (DNMT1) ...that maintains an altered methylation pattern by copying it from parent to daughter DNA strands after replication. Aberrant methylation of the promoter regions of genes critical for normal cellular functions is potentially reversible. Therefore, inactivation of DNMT1 seems to be a valuable target for the development of cancer therapies. Currently, the most popular DNMT inhibitors (DNMTi) are cytidine analogues like 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine) and pyrimidin-2-one ribonucleoside (zebularine). In colorectal cancer, epigenetic modifications play an essential role at each step of carcinogenesis. Therefore, we have addressed the hypothesis that DNA methyltransferase inhibitors may potentiate inhibitory effects of classical chemotherapeutic agents, such as oxaliplatin and 5-fluorouracil (5-FU), commonly used in colorectal cancer therapy. Here, our report shows that DNMTi can have positive interactions with standard chemotherapeutics in colorectal cancer treatment. Using pharmacological models for the drug-drug interaction analysis, we have revealed that the combination of decitabine with 5-FU or oxaliplatin shows the most attractive interaction (synergism), whereas the effect of zebularine in combinations with chemotherapeutics is moderate and may be depended on genetic/epigenetic background of a cell line or secondary drug used in combination. Our results suggest that DNMTi administered in combination with standard chemotherapeutics might improve the treatment of patients with colorectal cancers.
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