Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia

Grzybowska–Izydorczyk, Olga; Cebula, Barbara; Robak, Tadeusz; Smolewski, Piotr

doi:10.1016/j.ejca.2009.11.023

Cited by 57 publications

(44 citation statements)

References 40 publications

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“…Mean and SEM of 17 individual CLL samples measured in duplicate or triplicate (samples no. 2,6,8,12,15,17,18,19,24,28,33,36,39,41,43,48,50) 2,6,8,12,15,17,18,19,24,28,33,36,39,41,43,48,50) are shown; *p < 0.05. several solid tumors, 16,35,36,[51][52][53] while another study showed that CLL cells remain resistant against Smac mimetics in the context of CD40 ligand stimulation. 39 Compared with CLL cells, BV6 showed little cytotoxicity against non-malignant B-cells, a finding also reported by other investigators in CLL.…”

Section: Discussionmentioning

confidence: 99%

“…IAP proteins, in particular XIAP, are overexpressed in CLL and this overexpression confers chemoresistance and is associated with a progressive course. [11][12][13][14] To counter IAP proteins several small-molecule IAP inhibitors, including Smac mimetics, have been developed. 15 It has been shown that Smac mimetics abrogate XIAP-mediated caspase inhibition and induce autoubiquitination and rapid proteasomal degradation of cIAP1 and-2, leading to activation of NF-jB and TNFa production that triggers cell death in an autocrine/paracrine fashion.…”

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confidence: 99%

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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

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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...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

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“…However, these proteins seem to be responsible for resistance to apoptosis in cancer cells. The association between upregulation of IAP family proteins, such as XIAP, cIAP-1, cIAP-2 and survivin, and an unfavorable course of disease has been confirmed in chronic lymphocytic leukemia [12]. Also, pathological overexpression of IAP family members has been observed in various solid tumors including prostate cancer, breast cancer, pancreatic cancer, gastric cancer and melanoma [13][14][15][16][17][18].…”

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confidence: 87%

Expression of IAP family proteins and its clinical importance in breast cancer patients

Pluta¹,

Jeziorski²,

Cebula-Obrzut³

et al. 2015

neo

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Inhibitor of apoptosis (IAP) family proteins is involved in mechanisms of resistance to apoptosis in various cancer cells. The aim of this study was to assess the expression of selected IAP proteins such as XIAP, cIAP-1, cIAP-2 and survivin in breast cancer patients and evaluates their relationship with the prognostic and predictive factors and their impact to overall survival (OS) and progression free survival (PFS). The study was conducted with the use of tissue samples prospectively collected from 92 previously untreated female breast cancer patients. The control encompassed 10 fibroadenoma patients. The expression of XIAP, cIAP-1, cIAP-2 and survivin was assessed using flow multicolor cytometry. XIAP expression was present in 99 % of the breast cancer patients (91/92) with the median expression 13.65% (range 1-66.8%). Expression of XIAP in breast cancer was significantly higher compared to the control group (p=0.006). Median expression of cIAP-1, cIAP-2 and survivin in the study group was 25.95% (range 0.8-83.7%), 16.7% (range 1-53.2%) and 4.6% (range 0-43%) respectively. In the rank Spearman test, strong correlations (p<0.001) were seen among the expressions of XIAP, cIAP-2 and survivin, in all combination. Additionally, week correlation between XIAP and cIAP-1 was observed (p=0.02). The median expression of XIAP and survivin was significantly higher in more advanced tumors (stages pT2/pT3 vs. pT1). The median PFS and OS in breast cancer group were 46.15 and 47.1 months respectively. No significant correlations were observed among expressions of IAP family proteins and survival. However, low expression of XIAP in breast cancer showed trend to longer PFS (p=0.08). XIAP, cIAP-1 cIAP-2 and survivin participate in antiapoptotic mechanisms in breast cancer and XIAP and survivin seem to have the most significant prognostic importance. Further studies are needed to establish more complete prognostic and predictive values of IAP family proteins in breast cancer patients.

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“…However, downregulation of Smac has been also observed in CLL samples. Higher expression of IAPs and lower levels of Smac were found in patients with progressive disease, compared with those with stable CLL (Ren et al, 2006;Grzybowska-Izydorczyk et al, 2010).…”

Section: Chronic Lymphocytic Leukemia (Cll)mentioning

confidence: 95%

DIABLO (diablo, IAP-binding mitochondrial protein)

Ceballos‐Cancino¹,

Meléndez-Zajgla²

2013

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Expression and prognostic significance of the inhibitor of apoptosis protein (IAP) family and its antagonists in chronic lymphocytic leukaemia

Cited by 57 publications

References 40 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

Expression of IAP family proteins and its clinical importance in breast cancer patients

DIABLO (diablo, IAP-binding mitochondrial protein)

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