Suberoylanilide hydroxamic acid affects γH2AX expression in osteosarcoma, atypical teratoid rhabdoid tumor and normal tissue cell lines after irradiation

Blattmann, Claudia; Oertel, Susanne; Thiemann, Matthias; Weber, Klaus; Schmezer, Peter; Zelezny, O.; Perez, Ramon Lopez; Kulozik, Andreas E.; Debus, Jürgen; Ehemann, Volker

doi:10.1007/s00066-011-0028-5

Cited by 18 publications

(11 citation statements)

References 32 publications

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“…The combination of SAHA with IR showed radiosynergistic effects on overall clonogenic survival in all tested MB cell lines, even slightly stronger than found with VPA. Similarly, other groups observed a radiosensitizing action of SAHA on osteosarcoma and atypical teratoid rhabdoid tumor cells in vitro and in a rhabdoid tumor mouse model in vivo [ 61 , 62 ]. Regarding 5-aza-dC-treated irradiated MB cells, SAHA induced synergistic effects on overall clonogenic survival in all three tested MB cell lines and in this combination seems to be more effective than the HDACi VPA.…”

Section: Discussionmentioning

confidence: 79%

Enhanced inhibition of clonogenic survival of human medulloblastoma cells by multimodal treatment with ionizing irradiation, epigenetic modifiers, and differentiation-inducing drugs

Patties

Kortmann

Menzel

et al. 2016

J Exp Clin Cancer Res

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BackgroundMedulloblastoma (MB) is the most common pediatric brain tumor. Current treatment regimes consisting of primary surgery followed by radio- and chemotherapy, achieve 5-year overall survival rates of only about 60 %. Therapy-induced endocrine and neurocognitive deficits are common late adverse effects. Thus, improved antitumor strategies are urgently needed. In this study, we combined irradiation (IR) together with epigenetic modifiers and differentiation inducers in a multimodal approach to enhance the efficiency of tumor therapy in MB and also assessed possible late adverse effects on neurogenesis.MethodsIn three human MB cell lines (DAOY, MEB-Med8a, D283-Med) short-time survival (trypan blue exclusion assay), apoptosis, autophagy, cell cycle distribution, formation of gH2AX foci, and long-term reproductive survival (clonogenic assay) were analyzed after treatment with 5-aza-2′-deoxycytidine (5-azadC), valproic acid (VPA), suberanilohydroxamic acid (SAHA), abacavir (ABC), all-trans retinoic acid (ATRA) and resveratrol (RES) alone or combined with 5-aza-dC and/or IR. Effects of combinatorial treatments on neurogenesis were evaluated in cultured murine hippocampal slices from transgenic nestin-CFPnuc C57BL/J6 mice. Life imaging of nestin-positive neural stem cells was conducted at distinct time points for up to 28 days after treatment start.ResultsAll tested drugs showed a radiosynergistic action on overall clonogenic survival at least in two-outof-three MB cell lines. This effect was pronounced in multimodal treatments combining IR, 5-aza-dC and a second drug. Hereby, ABC and RES induced the strongest reduction of clongenic survival in all three MB cell lines and led to the induction of apoptosis (RES, ABC) and/or autophagy (ABC). Additionally, 5-aza-dC, RES, and ABC increased the S phase cell fraction and induced the formation of gH2AX foci at least in oneout-of-three cell lines. Thereby, the multimodal treatment with 5-aza-dC, IR, and RES or ABC did not change the number of normal neural progenitor cells in murine slice cultures.ConclusionIn conclusion, the radiosensitizing capacities of epigenetic and differentiation-inducing drugs presented here suggest that their adjuvant administration might improve MB therapy. Thereby, the combination of 5-aza-dC/IR with ABC and RES seemed to be the most promising to enhance tumor control without affecting the normal neural precursor cells.

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Section: Discussionmentioning

confidence: 79%

Enhanced inhibition of clonogenic survival of human medulloblastoma cells by multimodal treatment with ionizing irradiation, epigenetic modifiers, and differentiation-inducing drugs

Patties

Kortmann

Menzel

et al. 2016

J Exp Clin Cancer Res

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“…But despite the significantly higher technical complexity and higher costs, such patient-derived orthotopic xenografts models can better recapitulate the biology of the human disease and thus facilitating the investigation of novel treatment strategies in a setting that more closely resembles the human primary tumor [ 29 - 33 ]. We are currently employing this novel tool to identify new compounds for the systemic treatment of osteosarcoma and for developing new strategies to achieve local control by heavy ion radiotherapy [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a patient-derived orthotopic osteosarcoma mouse model

et al. 2015

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BackgroundOsteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue.MethodsFresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin.ResultsA primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established.ConclusionWe report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.

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“…In addition, HDACi may have a protective role in normal cells by suppressing the oncogenes, radiation-induced inflammatory cytokines, and stimulating the proliferation of stem cells [ 21 , 22 ]. Other factors such as extended phosphorylation of H2AX may be associated with this selective toxicity and radiosensitization [ 23 , 24 ]. Since cytotoxicity and radiation sensitivity often share the same mechanisms, SAHA’s radiosensitization effect may be also selective to cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Gerelchuluun

Maeda

Manabe

et al. 2018

IJMS

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Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

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Suberoylanilide hydroxamic acid affects γH2AX expression in osteosarcoma, atypical teratoid rhabdoid tumor and normal tissue cell lines after irradiation

Cited by 18 publications

References 32 publications

Enhanced inhibition of clonogenic survival of human medulloblastoma cells by multimodal treatment with ionizing irradiation, epigenetic modifiers, and differentiation-inducing drugs

Enhanced inhibition of clonogenic survival of human medulloblastoma cells by multimodal treatment with ionizing irradiation, epigenetic modifiers, and differentiation-inducing drugs

Establishment of a patient-derived orthotopic osteosarcoma mouse model

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

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