Enhanced Radiation-Induced Cell Killing and Prolongation of γH2AX Foci Expression by the Histone Deacetylase Inhibitor MS-275

Camphausen, Kevin; Burgan, William; Cerra, Michael; Oswald, Kelli; Trepel, Jane B.; Lee, Min-Jung; Tofilon, Philip J.

doi:10.1158/0008-5472.can-03-2630

Cited by 207 publications

(181 citation statements)

References 23 publications

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“…In contrast, there has been a lack of studies investigating the role of FLIP in regulating IR-induced apoptosis, possibly because early studies in Jurkat cells reported that FLIP was unable to prevent IR-induced apoptosis in this model (37). While some studies have unsurprisingly shown that FLIP regulates apoptosis in response to combined treatment with IR and TRAIL HDAC inhibitors such as vorinostat and entinostat prevent the deacetylation of histone and non-histone proteins and have been shown to sensitise cancer cells to chemotherapy and IR (41)(42)(43). In this study, we demonstrate that HDAC inhibitors enhance the in vitro and in vivo efficacy of IR in NSCLC models.…”

Section: Discussionmentioning

confidence: 51%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway.Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. KA McLaughlin et al. FLIP-mediated radio-resistance in NSCLC3

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Section: Discussionmentioning

confidence: 51%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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“…It is established that the g-H2AX form of the histone has an important role in recruiting repair factors to nuclear foci following induction of DSBs (Paull et al, 2000;Celeste et al, 2003;Olive and Banath, 2004). Recent studies have shown that incubation of cells with HDAC inhibitors including MS-275 and sodium butyrate, results in prolonged expression of induced g-H2AX foci (Camphausen et al, 2004a;Munshi et al, 2005). These findings indicate that HDAC inhibitor-mediated radiosensitization is associated with a decrease in the repair of DSBs.…”

Section: Mechanisms Of Hdac Inhibitor-mediated Enhanced Radiation Senmentioning

confidence: 96%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

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Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.

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“…In fact, HDACi can inhibit DNA repair responses in a few cell lines, which might increase the sensitivity of tumour cells to chemotherapy and radiotherapy by leading to increased DNA damage by these treatments 85,86 .…”

Section: The Cellular Effects Of Hdacimentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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Enhanced Radiation-Induced Cell Killing and Prolongation of γH2AX Foci Expression by the Histone Deacetylase Inhibitor MS-275

Cited by 207 publications

References 23 publications

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

Modulation of cellular radiation responses by histone deacetylase inhibitors

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

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