Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

Kim, R; Emi, Manabu; Matsuura, K.; Tanabe, Kazuaki

doi:10.1038/sj.cgt.7700986

Cited by 55 publications

(43 citation statements)

References 71 publications

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“…This triggers severe immunostimulatory response mechanism-like recognition by toll-like receptor 9 (TLR9) in the plasmacytoid dendritic cells (pDC), B-cell production of interferons and activation of both, natural killer cells (NK) and CD4 þ /CD8 þ T cells. 38 In summary, our data support the ability of wt1 to suppress apoptosis in leukemia cells. The expression of wt1 seems to be more important for cell survival than expression of the antiapoptotic gene bcl-2.…”

Section: Discussionsupporting

confidence: 62%

Effective treatment of leukemic cell lines with wt1 siRNA

et al. 2007

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The expression of wt1 and bcl-2 is considered to have a proliferating and survival supporting effect in leukemia blast cells. Here we describe the use of siRNA against wt1 and bcl-2 in leukemic cell lines for successful growth inhibition. We have used two different sequences designated as siRNA-A and siRNA-B corresponding to positions within the wt1 coding sequence to downregulate wt1 and a commercially available siRNA kit to downregulate bcl-2. WT1 and bcl-2 gene expression in transfected leukemic cell lines were evaluated with RT-PCR and western blot analyses. MTT assay was used to measure the cell viability and flow cytometry using annexin V/PI-staining for apoptosis. K562 and HL-60 cell lines transfected with siRNA-A targeted to wt1 had greatly decreased levels of both wt1 mRNA and protein expression. In contrast, siRNA-B and control siRNA led almost to no effect on wt1 mRNA and protein expression. siRNA-A-reduced wt1 mRNA expression was associated with a decreased cell proliferation and increased number of apoptotic cells in K562 and HL-60 cells by 24 and 48 h after transfection. Combined treatment with wt1 siRNA and bcl-2 siRNA simultaneously was not able to override the cell growth and apoptosis effects compared to single treatment with wt1 siRNA. siRNAs targeted against human wt1 might be a valuable tool as antiproliferative agent against wt1 expressing leukemic cells.

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Section: Discussionsupporting

confidence: 62%

Effective treatment of leukemic cell lines with wt1 siRNA

et al. 2007

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“…There were also some negative trial results, indicating that the agent was not effective and that it had toxic side-effects (55)(56)(57).…”

Section: Disease Target(s): Solid Tumors and Hematological Cancersmentioning

confidence: 99%

“…As noted in Box 1, Genasense has been under investigation in the clinic for many years, and may also still have a bright future. Its target (Bcl-2) has been implicated in numerous cancers, and the agent has shown promise in several clinical trials [57]. It is possible that this drug could eventually gain approval by the FDA.…”

Section: Clinical Trials Of Antisense Oligonucleotidesmentioning

confidence: 99%

Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

Rayburn

Zhang

2008

Drug Discovery Today

157

115

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Antisense oligonucleotides can regulate gene expression in living cells. As such, they regulate cell function and division, and can modulate cellular responses to internal and external stresses and stimuli. Although encouraging results from preclinical and clinical studies have been obtained and significant progress has been made in developing these agents as drugs, they are not yet recognized as effective therapeutics. Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects. The lessons learned from antisense drug development can help in the development of other oligonucleotide-based therapeutics such as CpG oligonucleotides, RNAi and miRNA. KeywordsAntisense; RNAi; Drug targeting; cancer; chemotherapy Historical perspectiveThe development of the antisense approach started in the late 1970s after the discovery that the expression of a specific gene product could be inhibited using a short complementary DNA sequence [1]. Since then, the antisense strategy has enjoyed exponential gains in interest and has been the subject of more than 16,000 publications. Between the appearance of the first publication about the antisense strategy in 1978 and the beginning of intensive antisense research (commencing in the early 1990s) very few studies were published. The increase in antisense research was largely a result of improvements in the methods used for DNA sequencing and synthesizing oligonucleotides [2,3]. Other major milestones in the development of antisense strategies include numerous discoveries about antisense chemistry. The most notable discovery was the addition of a phosphorothioate backbone to the *Correspondence and request for reprints to:

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“…[4][5][6][7] The antisense phosphorothioate oligonucleotide oblimersen is complementary to the first six codons of the open reading frame of the human Bcl-2 mRNA sequence and has been shown to downmodulate the Bcl-2 protein in pre-clinical studies using human cell lines of B-cell origin. 8 Clinically, oblimersen displayed modest single-agent activity in a phase I/II trial in heavily pretreated patients with CLL. 7 More importantly, oblimersen appears to potentiate the cytotoxic activity of agents commonly used in CLL.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Although the clinical efficacy of oblimersen combination therapy has been proven in this study, it is not clear as to whether its beneficial effect results from the downregulation of Bcl-2 in the leukemic cells and/or other non-antisense effects, including pro-inflammatory and immunomodulating actions. 8,10 We have recently performed a phase I/II study in patients with relapsed/refractory CLL using the novel antisense oligonucleotide SPC2996 (ClinicalTrials.gov Identifier: NCT00285103). SPC2996 is a representative of a new class of antisense reagents.…”

Section: Introductionmentioning

confidence: 99%

The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia

et al. 2011

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SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarraybased transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses X4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1a) and tumor necrosis factor-a, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a X50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects.

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Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

Cited by 55 publications

References 71 publications

Effective treatment of leukemic cell lines with wt1 siRNA

Effective treatment of leukemic cell lines with wt1 siRNA

Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

The novel antisense Bcl-2 inhibitor SPC2996 causes rapid leukemic cell clearance and immune activation in chronic lymphocytic leukemia

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