ArticleLeukemia2008
BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells.
Article in Leukemia, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 81 citations in OpenAlex.
- NF-κB Signaling in Prostate Cancer Progression: Inflammatory Mediators, Survival Pathways, and Regulatory Axes.Cancers · 2026Review
- GX15-070 enhances niraparib efficacy in ovarian cancer by promoting a shift in Mcl1-mediated DNA repair pathway from HR to NHEJ.Journal of translational medicine · 2025Article
- Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop.Communications biology · 2020Article
- Targeting BCL2 with venetoclax is a promising therapeutic strategy for "double-proteinexpression" lymphoma withHaematologica · 2019Article
- The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses.Cell death & disease · 2018Article
- Monitoring and Management of Toxicities of Novel B Cell Signaling Agents.Current oncology reports · 2018Review
- Article
- The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2017Review
- Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells.Oncotarget · 2016Article
- Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.British journal of pharmacology · 2016Article
- Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation.Frontiers in pediatrics · 2016Review
- Cell death induction by the BH3 mimetic GX15-070 in thyroid carcinoma cells.Journal of experimental & clinical cancer research : CR · 2015Article
- The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors.Endocrine-related cancer · 2015Review
- Know the enemy as well as the weapons in hand: the aberrant death pathways and therapeutic agents in chronic lymphocytic leukemia.American journal of cancer research · 2015Review
- Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia.Blood cancer journal · 2014Article
- Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Apoptosis inducers in chronic lymphocytic leukemia.Oncotarget · 2014Review
- RelB, together with RelA, sustains cell survival and confers proteasome inhibitor sensitivity of chronic lymphocytic leukemia cells from bone marrow.Journal of molecular medicine (Berlin, Germany) · 2014Article
- Bcl-2 antagonists: a proof of concept for CLL therapy.Investigational new drugs · 2013Review
- Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2.British journal of pharmacology · 2013Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.