p53 mRNA is not induced after 5-aza-CdR treatment. A, HCT116 and RKO...
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Article & May 2001
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In our experimental settings, 5-azanucleosides did not cause considerable immediate toxic effects on CRC cells. HCT116 cells appeared to be the most sensitive of all tested cell lines to 5-azanucleosides, which is consistent with the previous report [32] . Topoisomerase inhibitors operate by stabilizing the covalent DNA-topoisomerase cleavage complexes, thereby generating DNA single-and double-strand breaks and ultimately leading to apoptosis [33, 34] . ABSTRACT: Background: The currently approved therapies fail in a substantial number of colorectal cancer (CRC) patients due to the molecular heterogeneity of CRC, hence new efficient drug combinations are urgently needed. Emerging data indicate that 5-azanucleosides are able to sensitize cancer cells to the standard chemotherapeutic agents and contribute to overcoming intrinsic or acquired chemoresistance.
Methods: CRC cells with different genetic backgrounds (HCT116, DLD-1, HT-29) were sequentially treated with 5-azanucleosides and topoisomerase inhibitors. The combined effects of these two drug classes on cell viability, apoptosis, signaling pathways, and colony formation were investigated.
Results: Here, we demonstrate that pretreatment with DNA demethylating agents, 5-aza-2′-deoxycytidine and 5-azacytidine, sensitizes CRC cells to topoisomerase inhibitors (irinotecan, etoposide, doxorubicin, mitoxantrone), reducing cell viability and clonogenicity and increasing programmed cell death more effectively than individual compounds at the same or even higher concentrations. 5-Azanucleosides did not cause considerable immediate toxic effects as evaluated by analysis of cell viability, apoptosis, DNA damage (γH2A.X), and endoplasmic reticulum (ER) stress (CHOP). However, 5-azanucleosides exerted long-lasting effects, reducing cell viability, changing cell morphology, and affecting phosphoinositide 3-kinase (PI3-kinase)/Akt signaling pathway. We found that a single exposure to 5-azanucleosides is sufficient to induce long-lasting sensitization to topoisomerase inhibitors. The combinatorial, but not separate, treatment with low doses of 5-aza-2′-deoxycytidine (0.1 μM) and etoposide (0.5 μM) caused a long-lasting (almost 70 days) reduction in clonogenic/replating ability of DLD-1 cells.
Conclusions: These results suggest that sequential treatments with DNA demethylating agents and topoisomerase inhibitors may exert clinically relevant anticancer effects. Full-text · Article · Nov 2016 +1 more author...Both demethylating drugs and HDAC inhibitors have been approved in hematologic malignancies [13][14][15]. In solid tumors, single agent therapy with either treatment strategy results in limited tumor response, possibly due to high drug doses of drugs causing significant toxicity as well as the poor pharmacokinetics of these drugs with limited bioavailability [16][17]. Combination therapy of demethylating drugs along with HDAC inhibitors has been previously shown to promote gene re-expression [18]. ABSTRACT: Purpose:
Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies.
Experimental design:
We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 75 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and &30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy.
Forty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median.
Conclusion:
In this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS. Full-text · Article · Jul 2015 +1 more author...SGI-110, a dinucleotide prodrug of decitabine and deoxyguanosine that protects the parent from deamination and thereby increases the systemic exposure, is currently in phase 2 for AML [16]. While the exact mechanisms of resensitization—and sensitization— remain unclear, the promiscuous demethylation activity of these DNMTIs, which hit multiple targets including the tumor suppressor gene p53 that downmodulates glycolysis, may alter or reset the tumor biology and thwart chemoresistance171819. ABSTRACT: In cancer chemotherapy, one axiom, which has practically solidified into dogma, is that acquired resistance to antitumor agents or regimens, nearly inevitable in all patients with metastatic disease, remains unalterable and irreversible, rendering therapeutic rechallenge futile. However, the introduction of epigenetic therapies, including histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTIs), provides oncologists, like computer programmers, with new techniques to “overwrite” the modifiable software pattern of gene expression in tumors and challenge the “one and done” treatment prescription. Taking the epigenetic code-as-software analogy a step further, if chemoresistance is the product of multiple nongenetic alterations, which develop and accumulate over time in response to treatment, then the possibility to hack or tweak the operating system and fall back on a “system restore” or “undo” feature, like the arrow icon in the Windows XP toolbar, reconfiguring the tumor to its baseline nonresistant state, holds tremendous promise for turning advanced, metastatic cancer from a fatal disease into a chronic, livable condition. This review aims 1) to explore the potential mechanisms by which a group of small molecule agents including HDACis (entinostat and vorinostat), DNMTIs (decitabine and 5-azacytidine), and redox modulators (RRx-001) may reprogram the tumor microenvironment from a refractory to a nonrefractory state, 2) highlight some recent findings, and 3) discuss whether the current “once burned forever spurned” paradigm in the treatment of metastatic disease should be revised to promote active resensitization attempts with formerly failed chemotherapies. Full-text · Article · Oct 2014 +1 more author...HMAs may exert their effect through hypomethylation and induction of silenced tu however, when patients develop resistance to these drugs their hypomethylating effects are not lost [6]. In addition to DNA hypomethylation, both drugs have also been shown to induce DNA damage as a result of double strand DNA breaks resulting from the bulky adducts formed when DNMTs become trapped on azanucleoside-substituted DNA [7][8][9][10]. Despite clear demonstration of both events (i.e. ABSTRACT: The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen (CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust re-expression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy.Article · Sep 2014 +1 more author...p53 has been classically described as a mediator of IR cytotoxicity and acts by promoting either cell cycle arrest or apoptosis [27,28] . Previous studies have reported that 5- aza-dC induces p53 expression, which is associated with inhibition of cell proliferation in wild-type p53 cells but not in mutant p53 cells in prostate cancer [29,30]. However, because only a few cell lines and p53-associated molecules were examined in these studies, further research into the possible association of 5-aza-dC with p53 is necessary. ABSTRACT: Exposure of cells to ionizing radiation (IR) induces, not only, activation of multiple signaling pathways that play critical roles in cell fate determination, but also alteration of molecular pathways involved in cell death or survival. Recently, DNA methylation has been established as a critical epigenetic process involved in the regulation of gene expression in cancer cells, suggesting that DNA methylation inhibition may be an effective cancer treatment strategy. Because alterations of gene expression by DNA methylation have been considered to influence radioresponsiveness, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), on radiosensitivity. In addition, we investigated the underlying cellular mechanisms of combination treatments of ionizing irradiation (IR) and 5-aza-dC in human colon cancer cells. Colon cancer cell lines were initially tested for radiation sensitivity by IR in vitro and were treated with two different doses of 5-aza-dC. Survival of these cell lines was measured using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays. The effects of 5-aza-dC along with irradiation on cell growth, cell cycle distribution, apoptosis, and apoptosis-related gene expression were examined. Combination irradiation treatment with 5-aza-dC significantly decreased growth activity compared with irradiation treatment alone or with 5-aza-dC treatment alone. The percentage of HCT116 cells in the sub-G1 phase and their apoptotic rate was increased when cells were treated with irradiation in combination with 5-aza-dC compared with either treatment alone. These observations were strongly supported by increased caspase activity, increased comet tails using comet assays, and increased protein levels of apoptosis-associated molecules (caspase 3/9, cleaved PARP). Our data demonstrated that 5-aza-dC enhanced radiosensitivity in colon cancer cells, and the combination effects of 5-aza-dC with radiation showed greater cellular effects than that of single treatment, suggesting that the combination of 5-aza-dC and radiation has the potential to become a clinical strategy for the treatment of cancer. Full-text · Article · Aug 2014 +1 more author...When re-introducing wild-type p53 in those experiments, expression of these genes could be improved and when combined to azacitidine , normal expression of these genes could be restored [25,26]. Another study showed that colon tumor cell lines expressing wildtype p53 were more sensitive to azacitidine than those expressing mutant p53 [27]. Consequently, response to azacitidine could be worse in patients with mutant p53. ABSTRACT: TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p = 0.60 and p = 0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p & 10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p = 0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p = 0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p = 0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p = 0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR = 2.46 (95% confidence interval: 1.1-6.4); p = 0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.Article · Jul 2014 +1 more author...扫二维码下载作业帮
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