Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin

Newbold, Andrea; Lindemann, Ralph K.; Cluse, Leonie A.; Whitecross, Kate F.; Dear, Anthony E.; Johnstone, Ricky W.

doi:10.1158/1535-7163.mct-07-2256

Cited by 62 publications

(43 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pan-HDACi vorinostat and panobinostat modified survival, proliferation and differentiation, whereas the class-I-selective HDACi romidepsin predominantly reduced B-cell survival, leaving proliferation and differentiation intact. These selective differences are not unexpected, as romidepsin has been demonstrated to have a restricted set of targets when compared to pan-HDACi 47 and this specificity manifests at both the molecular 48 and functional level 49 .…”

Section: Discussionmentioning

confidence: 91%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

Self Cite

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

show abstract

Section: Discussionmentioning

confidence: 91%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar protection from chemotherapeutic drug-induced apoptosis can be afforded by overexpression of any of the other prosurvival BCL-2 family members. [134][135][136][137] Studies using gene-targeted mice or RNAi-mediated gene knockdown in cell lines revealed which pro-apoptotic BCL-2 family members are critical for cell killing by which anticancer agent. Consistent with the notion that BAX and BAK have essential overlapping functions in the BCL-2-regulated apoptotic pathway, cells from Bax −/− Bak −/− mice are markedly resistant to diverse anticancer agents.…”

Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

View full text Add to dashboard Cite

Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

show abstract

“…In vitro cell death and apoptosis analysis by flow cytometry Em-myc lymphoma cells (1 Â 10 5 ) were treated with compounds for 16 h in 96-well trays and the cell viability assessed by staining with 1 mg/ml propidium iodide (Sigma Aldrich Co, St Louis, MO, USA) (Newbold et al, 2008) and flow cytometry using the BD LSRII. Data were analysed using FACSExpress.…”

Section: Cell Culture and Transductionsmentioning

confidence: 99%

“…These data were used to calculate a best fit sigmoid dose-response curve using the statistical computing program 'R' (R DCT, 2009). Em-myc cells treated for 5 h were assessed for Annexin V APC (Becton Dickinson), and propidium iodide staining or assessed for DCM (MOMP) using tetramethyl-rhodamine ethyl ester (Invitrogen, Molecular Probes, Eugene, OR, USA) staining as described previously (Newbold et al, 2008). Cell cycle was analysed by DNA staining using propidium iodide on cells fixed in 95% ethanol at various times following drug treatment (Lindemann et al, 2007).…”

Section: Cell Culture and Transductionsmentioning

confidence: 99%

Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells

et al. 2011

View full text Add to dashboard Cite

CHK1 and CHK2 function as effectors of cell cycle checkpoint arrest following DNA damage. Small molecule inhibitors of CHK proteins are under clinical evaluation in combination with chemotherapeutic agents known to induce DNA damage. We examined whether CHK inhibitors could be effective as single agents in malignant cells with inherent DNA damage because of deregulated expression of the oncogene c-Myc. El-myc lymphoma cells showed a dramatic increase in the extent of DNA damage and DNA damage response (DDR) signalling within 1 h of treatment with CHK1 inhibitors followed by caspase-dependent apoptosis and cell death. In p53 wildtype/ARF null El-myc lymphoma cells, apoptotic cell death was preceded by accumulation of DNA damage and the amount of DNA damage correlated with the extent of cell death. This effect was not observed in normal B cells indicating that DNA damage accumulation following CHK inhibition was specific to El-myc lymphoma cells that exhibit inherent DNA damage because of MYCinduced replication stress. Similar results were obtained with another structurally distinct CHK-inhibitor. El-myc p53 null lymphoma cells were more sensitive to a dual CHK1/CHK2 inhibitor than to a CHK1-specific inhibitor. In all cases, the level of DNA damage following treatment was the most consistent indicator of drug sensitivity. Our results suggest that CHK inhibitors would be beneficial therapeutic agents in MYC-driven cancers. We propose that inhibitors of CHK can act in a synthetically lethal manner in cancers with replication stress as a result of these cancers being reliant on CHK proteins for an effective DDR and cell survival.

show abstract

Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin

Cited by 62 publications

References 19 publications

Manipulation of B-cell responses with histone deacetylase inhibitors

Manipulation of B-cell responses with histone deacetylase inhibitors

The BCL-2 protein family, BH3-mimetics and cancer therapy

Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells

Contact Info

Product

Resources

About