ABT-263 is a potent (K(i) < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L) and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 microM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 microM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. ABT-263 demonstrated in vitro activity ...Continue Reading
Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoietic progenitors
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis.
Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis
Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies.
Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA.
Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7
Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor.
BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly
In vivo evaluation of ixabepilone (BMS247550), a novel epothilone B derivative, against pediatric cancer models
Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo
The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis
Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members
Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737
The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo
Pediatric relapsed or refractory leukemia: new pharmacotherapeutic developments and future directions
BH3 response profiles from neuroblastoma mitochondria predict activity of small molecule Bcl-2 family antagonists
The novel Bcl-2 inhibitor ABT-737 is more effective in hypoxia and is able to reverse hypoxia-induced drug resistance in neuroblastoma cells
Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors
Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 as anticancer cell and antiangiogenic agents
Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts
Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199
Targeting the Bcl-2 family of proteins in Hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the Bcl-2 homology 3 mimetic ABT-737
The Bcl-2/Bax and Ras/Raf/MEK/ERK signaling pathways: implications in pediatric leukemia pathogenesis and new prospects for therapeutic approaches
Have chemosensitizing strategies for multidrug-resistant childhood acute lymphoblastic leukemia come of age?
S6K1 inhibition enhances the apoptotic cell death of breast cancer cells in response to Bcl-2/Bcl-xL inhibition by the downregulation of survivin
Induction of apoptosis in pediatric acute lymphoblastic leukemia (ALL) cells by the therapeutic opioid methadone and effective synergy with Bcl-2 inhibition
HPLC-MS/MS determination of a hardly soluble drug in human urine through drug-albumin binding assisted dissolution
Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo
Cytotoxicity, drug combinability, and biological correlates of ABT-737 against acute lymphoblastic leukemia cells with MLL rearrangement
ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro
Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy?
The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs
Haploinsufficiency of NR3C1 drives glucocorticoid resistance in adult acute lymphoblastic leukemia cells by down-regulating the mitochondrial apoptosis axis, and is sensitive to Bcl-2 blockage
GX15-070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma
Enabling cell recovery from 3D cell culture microfluidic devices for tumour microenvironment biomarker profiling
The Bcl-2/Bcl-X(L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo
Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts
Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines
Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.
BCL-2 Family Proteins
BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.
B-Cell Leukemia (Keystone)
B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.