Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma

Lindemann, Ralph K.; Newbold, Andrea; Whitecross, Kate F.; Cluse, Leonie A.; Frew, Ailsa J.; Ellis, Leigh; Williams, Steven P.; Wiegmans, Adrian P.; Dear, Anthony E.; Scott, Clare L.; Pellegrini, Marc; Wei, Andrew H.; Richon, Victoria M.; Marks, Paul A.; Lowe, Scott W.; Smyth, Mark J.; Johnstone, Ricky W.

doi:10.1073/pnas.0702294104

Cited by 189 publications

(218 citation statements)

References 29 publications

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“…Using the Eu-myc mouse model of B-cell lymphoma, vorinostat was found to selectively induce lymphoma cell death (in vivo), which was independent of p53 and death receptor pathways (Lindemann et al, 2007). Sensititivity to the HDACi was dependent on expression of the BH 3 -only proteins and BID and BIM.…”

Section: Hdaci Activates the Intrinsic Apoptotic Pathwaysmentioning

confidence: 98%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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Section: Hdaci Activates the Intrinsic Apoptotic Pathwaysmentioning

confidence: 98%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…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%

“…150,151 Furthermore, BMF as well as BIM are critical for the killing of non-transformed lymphoid cells as well as certain lymphoma cells by inhibitors of histone deacetylases. 110,135 BIM (with BAD and BMF also contributing) is critical for the killing of tumour cells that are dependent on oncogenic kinases by therapeutic agents that block their activity, such as inhibitors of MEK (acting downstream of mutant B-RAF in melanoma or colon carcinoma), 152 EGFR (lung cancer), [153][154][155] BCR-ABL (CML) 156,157 and VEGFR signalling (tumour angiogenesis). 158 Notably, a gene polymorphism that impairs the expression of BIM was found to explain the de novo resistance of BCR-ABL-driven CML to Gleevec and mutant EGFR-driven lung cancer to Iressa/ Tarceva in East Asian populations.…”

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

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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.

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“…The HDACi vorinostat (Zolinza) and romidepsin (Istodax) are FDA approved for the treatment of cutaneous T-cell lymphoma and trials are ongoing to determine the effectiveness of these drugs in other haematological diseases 18 . In addition, in experimental animal models, both B-cell and plasma-cell malignancies are sensitive to HDACi treatment 19,20 . The wealth of experimental data on the effect of HDACi on cancer cells including haematological malignancies, has progressed these compounds into the clinic.…”

mentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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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.

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Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma

Cited by 189 publications

References 29 publications

Histone deacetylase inhibitors: molecular mechanisms of action

Histone deacetylase inhibitors: molecular mechanisms of action

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

Manipulation of B-cell responses with histone deacetylase inhibitors

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