Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Ieranò, Caterina; Chakraborty, Arup; Nicolae, Alina; Bahr, Julian; Zhan, Zhirong; Pittaluga, Stefania; Bates, Susan E.; Robey, Robert W.

doi:10.4161/cc.25914

Cited by 25 publications

(24 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA damage as a dominant mechanism of action could explain some of the clinical observations, in particular, the lack of a sensitive subset that might be expected if there were a specific epigenetic lesion that was primarily targeted (Lemonnier et al, 2012;Palomero et al, 2014). Our in vitro work and that of others has shown that cell death is mediated via and dependent upon the intrinsic apoptotic pathway (Piekarz et al, 2004;Chen et al, 2009;J ona et al, 2011;Wiegmans et al, 2011;Chakraborty et al, 2013;Ierano et al, 2013). If this observation is correct, the combination of romidepsin with other agents that promote cell death via apoptotic pathways (Paoluzzi & O'Connor, 2010) should increase the response rates and response durations, provided increases in toxicity do not require reduction of cancer drug doses.…”

Section: Romidepsin In T-cell Lymphoma ª 2015 John Wiley and Sons Ltdmentioning

confidence: 76%

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Bates¹,

Eisch²,

Ling

et al. 2015

Br J Haematol

Self Cite

View full text Add to dashboard Cite

Summary Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to disease regression. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

show abstract

Section: Romidepsin In T-cell Lymphoma ª 2015 John Wiley and Sons Ltdmentioning

confidence: 76%

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Bates¹,

Eisch²,

Ling

et al. 2015

Br J Haematol

Self Cite

View full text Add to dashboard Cite

show abstract

“…It can be argued that the effect on chromatin (i.e., global histone acetylation leading to gene transcription) should be considered separately from the events leading to cell death. Furthermore, multiple laboratories have pointed to a critical role for apoptosis in effecting cell death following HDAC inhibitor exposure (89)(90)(91)(92). These studies suggest that HDAC inhibitor efficacy could be increased by the addition of agents increasing the propensity of cells to undergo apoptosis.…”

Section: Targeting the Epigenome In Ptclmentioning

confidence: 92%

Changing the Paradigms of Treatment in Peripheral T-cell Lymphoma: From Biology to Clinical Practice

O’Connor

Bhagat

Ganapathi

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits-all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/ lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis.

show abstract

“…A loss of Bcl-2 family proapoptotic protein expression has been previously reported to be involved in romidepsin resistance (39,40), and fenretinide has been shown to activate Bcl-2 family proapoptotic proteins in T-ALL cell lines (12). In TCLM cell lines, The cytotoxic synergy of ROM þ 4-HPR is mediated by ROS.…”

Section: Romidepsin þ Fenretinide (Mediated By Ros) Induced Proapoptomentioning

confidence: 98%

Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

Makena

Koneru

Nguyen

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). , romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)-dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs..

show abstract

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Cited by 25 publications

References 52 publications

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Changing the Paradigms of Treatment in Peripheral T-cell Lymphoma: From Biology to Clinical Practice

Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

Contact Info

Product

Resources

About