The sequence of application of methotrexate and histone deacetylase inhibitors determines either a synergistic or an antagonistic response in childhood acute lymphoblastic leukemia cells

Bastian, Lorenz; Einsiedel, Hagen Graf; Henze, Guenter; Seeger, Karl; Shalapour, Shabnam

doi:10.1038/leu.2010.259

Cited by 12 publications

(11 citation statements)

References 6 publications

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“…Both of our in-house cell lines, i.e., MBL-02 medulloblastoma and OSA-08 osteosarcoma cell lines, appeared to be strongly resistant to MTX; 100 μ M MTX did not induce a 50% inhibitory effect in these cells. One of the possible explanations for this difference is the low proliferation rate of these tumor cells in comparison with the reference cell lines ( 15 ). No observable effect of LV in these cell lines could be explained by the same mechanisms since treatment with MTX is targeted to quickly proliferating tumor cells.…”

Section: Discussionmentioning

confidence: 99%

DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: The same outcome of treatment with different doses in sensitive cell lines

et al. 2015

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Although methotrexate (MTX) is the most well-known antifolate included in many standard therapeutic regimens, substantial toxicity limits its wider use, particularly in pediatric oncology. Our study focused on a detailed analysis of MTX effects in cell lines derived from two types of pediatric solid tumors: medulloblastoma and osteosarcoma. The main aim of this study was to analyze the effects of treatment with MTX at concentrations comparable to MTX plasma levels in patients treated with high-dose or low-dose MTX. The results showed that treatment with MTX significantly decreased proliferation activity, inhibited the cell cycle at S-phase and induced apoptosis in Daoy and Saos-2 reference cell lines, which were found to be MTX-sensitive. Furthermore, no difference in these effects was observed following treatment with various doses of MTX ranging from 1 to 40 μM. These findings suggest the possibility of achieving the same outcome with the application of low-dose MTX, an extremely important result, particularly for clinical practice. Another important aspect of treatment with high-dose MTX in clinical practice is the administration of leucovorin (LV) as an antidote to reduce MTX toxicity in normal cells. For this reason, the combined application of MTX and LV was also included in our experiments; however, this application of MTX together with LV did not elicit any detectable effect. The expression analysis of genes involved in the mechanisms of resistance to MTX was a final component of our study, and the results helped us to elucidate the mechanisms of the various responses to MTX among the cell lines included in our study.

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Section: Discussionmentioning

confidence: 99%

DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: The same outcome of treatment with different doses in sensitive cell lines

et al. 2015

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“…Changes in the order of application can substantially alter the effect of drug combinations, as we have previously shown for the combination of HDACi and methotrexate (8). Therefore, we analyzed whether the sequence of application has an effect on drug responsiveness to bortezomib and HDACi.…”

Section: Concomitant Treatment With Bortezomib and Hdaci Has Synergismentioning

confidence: 94%

“…So far, only additive or even antagonistic interactions have been observed after combined treatment with HDACi and different conventional cytostatic drugs in myeloid leukemia and T-ALL cells (7). In BCP-ALL leukemia cells, we have recently observed that the sequence of drug application determined synergistic or antagonistic responses to combined treatment with HDACi and methotrexate (8).…”

Section: Introductionmentioning

confidence: 99%

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Bastian

Hof

Pfau

et al. 2013

Clinical Cancer Research

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Purpose: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients.Experimental Design: Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation.Results: We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-kB pathways. We observed an activation of NF-kB after bortezomib treatment and the induction of apoptosis-related NFkB target genes such as TNFaRs after concomitant treatment, indicating a possible involvement of NF-kB as proapoptotic mediator. In this context, significantly lower NF-kB subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy.Conclusion: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols.

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“…As with nearly all new drugs, HDAC inhibitors are proposed for combination therapy to strengthen therapeutic efficacy as well as to minimize chemoresistance. Valproic acid has been studied in combination with several cytotoxic drugs, such as methotrexate or epirubicin, for synergistic or antagonistic effects in other types of cancer (127, 128). Belinostat (PDX101), a novel HDAC inhibitor in the hydroxamic acid group, displayed anticancer effects as a single agent as well as in combination by increasing the acetylation of tubulin induced by docetaxel and the phosphorylation of H2AX induced by carboplatin (129).…”

Section: Epigenetic Therapy In Ovarian Cancermentioning

confidence: 99%

Molecular Epigenetics in the Management of Ovarian Cancer: Are We Investigating a Rational Clinical Promise?

2014

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Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. Although liquid tumors are benefiting from epigenetically related therapies, solid tumors like ovarian cancer are not (yet?). Herein, we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Pre-clinical and clinical research on the role of epigenetic modifications is also summarized. Unfortunately, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management, which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have pre-clinical utility in pharmacology and clinical applications for prognosis and diagnosis. Finally, drugs currently in clinical trials (i.e., histone deacetylase inhibitors) are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; but we hope so in the future.

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The sequence of application of methotrexate and histone deacetylase inhibitors determines either a synergistic or an antagonistic response in childhood acute lymphoblastic leukemia cells

Cited by 12 publications

References 6 publications

DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: The same outcome of treatment with different doses in sensitive cell lines

DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: The same outcome of treatment with different doses in sensitive cell lines

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Molecular Epigenetics in the Management of Ovarian Cancer: Are We Investigating a Rational Clinical Promise?

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