Single-agent Smac-mimetic compounds induce apoptosis in B chronic lymphocytic leukaemia (B-CLL)

Scavullo, Cinzia; Servida, Federica; Lecis, Daniele; Onida, Francesco; Drago, Carmelo; Ferrante, Luca; Seneci, Pierfausto; Barcellini, Wilma; Lionetti, Marta; Todoerti, Katia; Neri, Antonino; Delia, Domenico; Deliliers, Giorgio Lambertenghi

doi:10.1016/j.leukres.2013.03.016

Cited by 9 publications

(15 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, BV6 exceeds Fludarabine's antileukemic activity especially in resistant samples with TP53 mutation or 17p deletion, which is associated with loss of p53. While some other studies using different Smac mimetics reported no correlation between cell death induction by Smac mimetic and biological parameters in primary CLL, 39,40 two studies using IAP inhibitors plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) showed cell death induction in CLL cases with poor prognosis. 13,41 Using whole-genome gene expression profiling, we identify two functional categories that are most significantly modulated by BV6, i.e., programmed cell death and NF-jB pathway, across tumor entities not only in CLL but also in primary CBF AML samples, underlining the broader relevance of this finding.…”

Section: Discussionmentioning

confidence: 97%

“…45 Furthermore, no elevated TNFa levels were found in our GEP analysis, while this has previously been observed by other investigators in CLL cells upon treatment with another Smac mimetic. 40 Second, BV6-induced cell death is caspase-independent, because zVAD.fmk is unable to protect CLL cells from BV6-triggered cell death and even significantly increases cell death, pointing to a caspase-independent mode of cell death, for example, necroptosis. However, the RIP1 kinase inhibitor Nec-1 fails to inhibit BV6-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

“…31,48,49 Our findings showing that BV6 cooperates together with Obatoclax to induce cell death in CLL cells, but not together with ABT-263 may be related to the differential activity profiles of these BH3 mimetics, as Obatoclax antagonizes BCL-2, BCL-xL, BCL-W and MCL-1, whereas ABT-263 targets BCL-2, BCL-xL and BCL-W, but not MCL-1. 50 Single-agent cytotoxicity of Smac mimetic compounds has been reported for CLL, 40 multiple myeloma or 2, 12, 17, 39) were treated for indicated times with 10 mM BV6, 1 mM Staurosporine and 20 mM zVAD.fmk alone or in combination. Caspase-3 activity was determined by FACS analysis using 100 mM rhodamine-conjugated zDEVD substrate after 30 min of incubation at 378C.…”

Section: Discussionmentioning

confidence: 99%

“…39 Compared with CLL cells, BV6 showed little cytotoxicity against non-malignant B-cells, a finding also reported by other investigators in CLL. 40 As there is so far no evidence of a cell cycle dependency of Smac mimetic-induced cytotoxicity, Smac mimetics are of interest also for malignancies with a low proliferative capacity.…”

Section: Discussionmentioning

confidence: 99%

“…Mean and SEM of 18 individual CLL samples measured in duplicate or triplicate (samples no. 2,6,8,15,17,18,19,21,24,28,33,36,39,40,41,43,48,50) are shown; **p < 0.001; *p < 0.05; (right) Graph illustrates specific cell death upon treatment with 10 mM Fludarabine or BV6 of genomic subgroups including norm/13q-, IGVH non-mutated, tp53 mutated and 17p deletion. (e and f) BV6-sensitive primary CLL cells were co-treated with 10 mM BV6 and 1,000 ng/ml CD40 ligand (e) or stimulated with BV6 in normal or conditioned medium at indicated concentrations (f) for 48 hr.…”

Section: Bv6 Induces Cell Death In Primary Cll Cells Irrespective Of mentioning

confidence: 99%

See 4 more Smart Citations

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Bv6 Induces Cell Death In Primary Cll Cells Irrespective Of mentioning

confidence: 99%

See 3 more Smart Citations

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum‐resistant or ‐refractory epithelial ovarian cancer

Noonan

Bunch

Chen

et al. 2015

Cancer

View full text Add to dashboard Cite

Background Inhibitors of Apoptosis Proteins (IAPs) are key regulators of apoptosis, and are frequently dysregulated in ovarian cancer. We hypothesized that blocking IAPs with birinapant would increase tumor cell death resulting in objective response for women with platinum-refractory and resistant ovarian cancer. Methods In this phase II CTEP-sponsored study, patients received birinapant 47mg/m2 on days 1, 8, 15 of 28-day cycles. Pharmacokinetics were obtained in cycle 1. Plasma, peripheral blood mononuclear cells (PBMC) and percutaneous tumor biopsies were collected prior to cycle 1, and after 6 weeks. The primary endpoint was objective response or progression-free survival lasting greater than 6 months in a mini-max design. Results Eleven patients received birinapant, after which accrual was terminated for lack of clinical benefit. Birinapant was well-tolerated, with predominantly grade 2 adverse events (AE) and one grade 3 lymphopenia. Pre-treatment biopsies and PBMCs were collected; paired post-treatment biopsies and PBMC were collected from 7 and 10 patients, respectively. There was consistent downregulation of cIAP1 in tumor (P=0.016) and PBMC (P<0.01). Pro-caspase3 also decreased in tumors (P=0.031) and PBMC (P<0.01); cleaved caspase3 co-localized with gamma-H2AX in tumors after birinapant exposure. Peripheral T- and B-cells decreased significantly post-treatment, but NK-cells did not (P=0.04, P=0.05, P=0.43 respectively). Conclusion Birinapant shows consistent target suppression in vivo, without single agent anti-tumor activity in this small population. Single agent pharmacodynamics were necessary to understand drug mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.

show abstract

Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia

et al. 2016

View full text Add to dashboard Cite

SMAC-mimetics represent a targeted therapy approach to overcome apoptosis resistance in many tumors. Here, we investigated the efficacy of the SMAC-mimetic BV6 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In ALL cell lines, intrinsic apoptosis sensitivity was associated with rapid cIAP degradation, NF-κB activation, TNF-α secretion and induction of an autocrine TNF-α-dependent cell death loop. This pattern of responsiveness was also observed upon ex vivo analysis of 40 primograft BCP-ALL samples. Treatment with BV6 induced cell death in the majority of ALL primografts including leukemias with high-risk and poor-prognosis features. Inhibition of cell death by the TNF receptor fusion protein etanercept demonstrated that BV6 activity is dependent on TNF-α. In a preclinical NOD/SCID/huALL model of high-risk ALL, marked anti-leukemia effectivity and significantly prolonged survival were observed upon BV6 treatment. Interestingly, also in vivo, intrinsic SMAC-mimetic activity was mediated by TNF-α. Importantly, BV6 increased the effectivity of conventional induction therapy including vincristine, dexamethasone and asparaginase leading to prolonged remission induction. These data suggest SMAC-mimetics as an important addendum to efficient therapy of pediatric BCP-ALL.

show abstract

Single-agent Smac-mimetic compounds induce apoptosis in B chronic lymphocytic leukaemia (B-CLL)

Cited by 9 publications

References 33 publications

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum‐resistant or ‐refractory epithelial ovarian cancer

Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia

Contact Info

Product

Resources

About