Targeting inhibitor of apoptosis proteins by <scp>S</scp>mac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel, Daniela; Schnaiter, Andrea; Dodier, Dagmar; Jovanovic, Marjana; Gerhardinger, Andreas; Idler, Irina; Mertens, Daniel; Bullinger, Lars; Stilgenbauer, Stephan; Fulda, Simone

doi:10.1002/ijc.29650

Cited by 18 publications

(7 citation statements)

References 54 publications

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“…52 Multiple lines of evidence have recently reported the success of SMAC mimetics in cancer combination therapy. [53][54][55][56][57][58] Accordingly, it was worth in this study to investigate the sensitizing effect of BV6 on TNF (recombinant human TNF-a) and killer TRAIL (a highly active form of TRAIL) in different cell lines.…”

Section: Discussionmentioning

confidence: 99%

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

El-Mesery

Shaker

Elgaml

2016

Exp Biol Med (Maywood)

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The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF-kappa B (NF-kB) pathway, as indicated by stabilizing NF-kB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-a (TNF-a) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.

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Section: Discussionmentioning

confidence: 99%

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

El-Mesery

Shaker

Elgaml

2016

Exp Biol Med (Maywood)

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“…Of note, we recently identified by GEP cell death and NF-κB among the top pathways regulated by BV6 in responsive primary CLL samples as well as in primary core-binding factor (CBF) AML samples [38], underscoring the general relevance of these signaling pathways for Smac mimetic-mediated antitumor activity. While that study also revealed redox signaling as another pathway in BV6-sensitive primary CLL samples as well as in primary CBF AML samples [38], we did not find redox-related signaling cascades among the top regulated pathways in the present set of AML samples, pointing also to some differences among these types of leukemia.…”

Section: Discussionmentioning

confidence: 99%

Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers

et al. 2016

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Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.

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“…The cells were harvested and analyzed for apoptosis by flow cytometry. In another experiment, tumor cells prepared in 24-well plates were treated for 24 and 48 hours with IFNg (250 IU/mL; ImmunoTools) and TNFa (30 ng/mL) or 20% of supernatant obtained from Th1 (H68 clone 97), Th2 (H68 clone 133), or Th17 (H68 clone 103) cells with or without the addition of apoptosis inducer and cIAP1/2-interacting compound BV6 (5 mmol/L smac mimetic; ApexBio) and pan-caspase inhibitor zVADfmk (20 mmol/L FMK001; R&D Systems), together known to induce necroptosis (17)(18)(19). Necrostatin (Nec)-1s (2263-1; BioVision) was added to the conditions used for UM-SCC19 to inhibit necroptosis via inhibition of RIP1K (14).…”

Section: Tils and Tumor Cell Analysesmentioning

confidence: 99%

Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer

Welters

Santegoets

et al. 2018

Clinical Cancer Research

134

193

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Purpose: Human papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC, and this is linked to dense tumor immune infiltration. As the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in the tumor microenvironment, and clinical outcome.Experimental Design: To this purpose, an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 patients with HPV16-positive and HPV16-negative OPSCC was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry, and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 patients with HPV16-positive OPSCC present in the publicly available The Cancer Genome Atlas database.Results: In 64% of the HPV16-positive tumors, type I HPV16-specific T cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size, and less lymph node metastases but also to a type I-oriented tumor microenvironment, including high numbers of activated CD161 þ T cells, CD103 þ tissue-resident T cells, dendritic cells (DC), and DC-like macrophages. Conclusions:The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process. Clin Cancer Res; 24(3); 634-47. Ó2017 AACR.

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

Cited by 18 publications

References 54 publications

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers

Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer

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