The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

Lemoine, Manuela; Derenzini, Enrico; Buglio, David Lo; Medeiros, L. Jeffrey; Davis, R. Eric; Zhang, Jiexin; Ji, Yuan; Younes, Anas

doi:10.1182/blood-2011-01-331421

Cited by 78 publications

(76 citation statements)

References 23 publications

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“…For example, class II HDAC6 and HDAC4 are associated with HIF-1α, and inhibition of both HDACs reduces HIF-1α protein levels (Geng et al 2011;Kong et al 2006;Qian et al 2006). Interestingly, treating cells with histone deacetylase inhibitor (HDACi) also reduces HIF-1α at the protein level under normoxic, hypoxic, and hypoxia mimic conditions (Kim et al 2001;Kong et al 2006;Lemoine et al 2012;Qian et al 2006). For example, TSA repressed HIF-1α levels in HCT116 cells (p53 +/+ ) and in isogenic p53 −/− HCT116-derived cells.…”

Section: Introductionmentioning

confidence: 99%

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

Ryu

Won

Lee

et al. 2017

Cell Stress and Chaperones

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Histone deacetylase 6 (HDAC6) plays an important role in stress responses such as misfolded protein-induced aggresomes, autophagy, and stress granules. However, precisely how HDAC6 manages response during and after cellular stress remains largely unknown. This study aimed to investigate the effect of HDAC6 on various stress and poststress recovery responses. We showed that HIF-1α protein levels were reduced in HDAC6 knockout (KO) MEFs compared to wild-type (WT) MEFs in hypoxia. Furthermore, under hypoxia, HIF-1α levels were also reduced following rescue with either a catalytically inactive or a ubiqiutin-binding mutant HDAC6. HDAC6 deacetylated and upregulated the stability of HIF-1α, leading to activation of HIF-1α function under hypoxia. Notably, both the deacetylase and ubiquitinbinding activities of HDAC6 contributed to HIF-1α stabilization, but only deacetylase activity was required for HIF-1α transcriptional activity. Suppression of HDAC6 enhanced the interaction between HIF-1α and HSP70 under hypoxic conditions. In addition to hypoxia, depletion of HDAC6 caused hypersensitivity to cell death during oxidative stress and post-stress recovery. However, HDAC6 depletion had no effect on cell death in response to heat shock or ionizing radiation. Overall, our data suggest that HDAC6 may serve as a critical stress regulator in response to different cellular stresses.

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Section: Introductionmentioning

confidence: 99%

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

Ryu

Won

Lee

et al. 2017

Cell Stress and Chaperones

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“…[97][98][99][100][101] Panobinostat is a potent pan-HDAC inhibitor with activity in Hodgkin lymphoma. 102 In a phase II study by Younes et al, 103 heavily pretreated relapsed or refractory Hodgkin patients were administered panobinostat 40 mg orally three times per week.…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?

Epperla

Fenske

Lazarus

et al. 2015

Bone Marrow Transplant

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Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5-and 10-year PFS rates are~60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton's tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT.

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“…Everolimus is also synergistic with other agents. 38,42,43 Immunomodulatory therapy Lenalidomide is an immunomodulatory agent with several mechanisms of action. 27 Limited data suggest that lenalidomide has modest clinical activity in relapsed/refractory HL (Table 1).…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all!

Kharfan‐Dabaja

Hamadani

Sibai

et al. 2014

Bone Marrow Transplant

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Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25-35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.

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The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

Cited by 78 publications

References 23 publications

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?

Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all!

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