Different Effects of Epigenetic Modifiers on the Cytotoxicity Induced by 5-Fluorouracil, Irinotecan or Oxaliplatin in Colon Cancer Cells

Ikehata, Mika; Ogawa, Mitsuhiro; Yamada, Y.; Tanaka, Shota; Iwakawa, Seigo

doi:10.1248/bpb.b13-00574

Cited by 34 publications

(25 citation statements)

References 24 publications

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“…5-Aza-2'-deoxycytidine (DAC) is a DNA methyltransferase (DNMT) inhibitor, a DNA demethylating agent, and a cell cycle-arresting agent (7)(8)(9). Preliminary studies have been conducted on the combined use of DNMT inhibitors with existing antitumor agents (10)(11)(12). Accordingly, a preliminary experiment was conducted on a combination of a specific antitumor agents, including CPT-11, SN-38 or 5-FU with one of several epigenetic modifiers including DAC in two different human CRC cell lines; HCT116 and HT29 (13).…”

Section: Introductionmentioning

confidence: 99%

Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

et al. 2018

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Abstract. Irinotecan (CPT-11) is a key therapeutic drug used in the treatment of colorectal cancer, although acquired or constitutive resistance to CPT-11 (and its activated metabolite SN-38) can lead to tumor progression. Since the acquisition of drug resistance can result from DNA hypermethylation, the antitumor activity of CPT-11 and SN-38 was assessed in combination with a known DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, also known as decitabine (DAC). DAC potentiated the antitumor activity of CPT-11 additively, and that of SN-38 synergistically, as measured by colony formation in the human colorectal cancer HCT116 cell line. No DAC potentiation of these antitumor effects was observed with another human colorectal cancer HT29 cell line. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein expression was reduced to 50-67% of the control following a single treatment with CPT-11, SN-38, or DAC, and was markedly reduced to 7-8% following the combination of CPT-11/SN-38 with DAC. By contrast, Bcl-2 protein expression was barely detected in HT29. Wilms' tumor protein (WT1), which has been shown to be a positive regulator of Bcl-2 in HCT116 cells through WT1-kncokdown experiments, was downregulated in HCT116 and HT29 cells when treated with CPT-11/SN-38 combined with DAC, with decreases greater than any single administration of CPT-11, SN-38, or DAC. The extent of CPT-11/SN-38 potentiation by DAC may depend on Bcl-2 expression levels in human colorectal cancer cells.

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Section: Introductionmentioning

confidence: 99%

Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

et al. 2018

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“…44 Regarding epi-drugs, it has been recently highlighted their capability (mostly HDACi and DNMTi) 45,46 to increase chromatin accessibility to conventional DNA-damaging chemotherapeutic agents, markedly enhancing their effects and establishing a rationale for their combination. Several pieces of evidence showed that the CpG island methylation is responsible for the induction of drug resistance, and this effect can be reversed through the treatment with hypomethylating agents [47][48][49][50] including zebularine 50 and decitabine 2. 50,51 The combination of HDACi with cytostatic agents (such as doxorubicin and paclitaxel) has been widely evaluated in both preclinical and clinical contexts.…”

Section: The Mmt Approachmentioning

confidence: 99%

“…Several pieces of evidence showed that the CpG island methylation is responsible for the induction of drug resistance, and this effect can be reversed through the treatment with hypomethylating agents [47][48][49][50] including zebularine 50 and decitabine 2. 50,51 The combination of HDACi with cytostatic agents (such as doxorubicin and paclitaxel) has been widely evaluated in both preclinical and clinical contexts. Here, a reliable increase in the therapeutic outcome was achieved, due to the downregulation of proangiogenic and tumorigenic factors (ie, hypoxia-inducible factor 1 [HIF-1α] and vascular endothelial growth factor [VEGF]), 52,53 the repression of DNA repair systems 54 as well as the enhancement of apoptosis induction.…”

Section: The Mmt Approachmentioning

confidence: 99%

“…For these compounds, the ability to bind also BET bromodomain has been reported (IC 50 [299][300][301] Starting from SAR studies focused on 70 (Figure 8 (Figure 9) and the benzamide 73 304 (MC2392; Figure 9), strictly related to ATRA, to be tested in leukemia. While 72 did not show any significant activity in leukemia cells, 73, despite its weak retinoid activity and general no HDAC inhibition in vitro and in vivo, was able to induce changes in H3 acetylation at a small subset of PML-RARα-binding sites, to alter expression of stress-responsive and apoptotic genes, and to induce massive cell death specifically in PML-RARα expressing APL cells, while solid and other leukemic tumors were not affected.…”

Section: Dual Bet/kinase Inhibitorsmentioning

confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…All the experiments were carried out in triplicate. By the method of Chou and Talalay, [35][36][37] the combination indexes (CIs) isobologram were calculated and plot with Calcusyn software, and a CI value >1, CI value=1, and CI value <1 mean antagonism, additivity, or synergism, respectively.…”

Section: Mtt Assay and Examination Of Drug Combinationmentioning

confidence: 99%

Synergistic Anti-glioma Effects in Vitro and in Vivo of Enediyne Antibiotic Neocarzinostatin and Paclitaxel via Enhanced Growth Delay and Apoptosis-Induction

Tianqin

Chen²,

Wang

2016

Biological & Pharmaceutical Bulletin

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Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.

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Different Effects of Epigenetic Modifiers on the Cytotoxicity Induced by 5-Fluorouracil, Irinotecan or Oxaliplatin in Colon Cancer Cells

Cited by 34 publications

References 24 publications

Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

Differential sensitization of two human colon cancer cell lines to the antitumor effects of irinotecan combined with 5-aza-2'-deoxycytidine

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Synergistic Anti-glioma Effects <i>in Vitro</i> and <i>in Vivo</i> of Enediyne Antibiotic Neocarzinostatin and Paclitaxel <i>via</i> Enhanced Growth Delay and Apoptosis-Induction

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