XIAP-mediated Caspase Inhibition in Hodgkin's Lymphoma–derived B Cells

The malignant Hodgkin and Reed-Sternberg cells of Hodgkin's lymphoma (HL) and HL-derived B cell lines were previously shown to be resistant to different apoptotic stimuli. We show here that cytochrome c fails to stimulate caspases-9 and -3 activation in cytosolic extracts of HL-derived B cells, which is due to high level expression of X-linked inhibitor of apoptosis (XIAP). Coimmunoprecipitation studies revealed that XIAP, apoptosis protease-activating factor–1, and caspase-3 are complexed in HL-derived B cell lysates. Even after stimulation with exogenous cytochrome c and dATP, XIAP impairs the proteolytic processing and activation of caspase-3. In cytosolic extracts, inhibition of XIAP by the second mitochondria-derived activator of caspases (Smac)/DIABLO, or immunodepletion of XIAP restores cytochrome c–triggered processing and activation of caspase-3. Smac or a Smac-derived agonistic peptide also sensitized intact HL-derived B cells for the apoptotic action of staurosporine. Finally, Hodgkin and Reed-Sternberg cells of primary tumor HL tissues also constitutively and abundantly express XIAP. The results of this paper suggest that high level XIAP expression is a hallmark of HL, which may play a crucial role in resistance to apoptosis

Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitor may address some limitations

Phase III Randomized Trial Comparing the Efficacy of Cediranib as Monotherapy and in Combination With Lomustine Versus Lomustine Alone in Patients With Recurrent Glioblastoma

Purpose: A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. Patients and Methods: Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m2); (3) lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. Results: The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. Conclusion: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects

Bcl-2 family proteins and mitochondria

AbstractThe Bcl-2 family of proteins plays a pivotal role in regulating cell life and death. Many of these proteins reside in the outer mitochondrial membrane, oriented towards the cytosol. Cytoprotective Bcl-2 family proteins such as Bcl-2 and Bcl-XL prevent mitochondrial permeability transition pore opening and release of apoptogenic proteins from mitochondria under many circumstances that would otherwise result in either apoptosis or necrosis. In contrast, some pro-apoptotic members of this family such as Bax can induce these destructive changes in mitochondria in both mammalian cells and when expressed exogenously in yeast. The mechanisms by which Bcl-2 family proteins control cell life and death remain elusive, but may include both the ability to form ion channels or pores in membranes and physical interactions with a variety of proteins implicated in apoptosis regulation

Antitumor and antiangiogenic activity of cediranib in a preclinical model of renal cell carcinoma

Cediranib is a highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor with activity against all three VEGF receptors (VEGFRs) that inhibits angiogenesis and growth of human tumor xenografts in vivo. The present study evaluated the antitumor and antiangiogenic activity of cediranib in the clinically relevant, murine renal cell carcinoma (RENCA) model and its biological response using VEGF and sVEGFR-2 as biomarkers. Mice were treated with cediranib (5 mg/kg/d p.o.) or vehicle for 2, 8 or 12 days and tumor volumes, microvessel density (MVD) and VEGF and sVEGFR-2 plasma concentrations were determined. Cediranib treatment (8 and 12 days) led to a significant reduction in tumor size (42-50%) and a highly significant reduction in MVD (30-55%) versus controls. After 12 days' treatment, VEGF plasma concentration increased significantly in both cediranib-treated and control animals and this increase correlated with tumor size; the cediranib group showed a more pronounced increase in VEGF but a reduced tumor volume compared with control animals. Plasma concentrations of VEGF reached a plateau in the cediranib group after 17-21 days' treatment. sVEGFR-2 concentrations significantly decreased over 12 days in controls, whereas they remained stable in cediranib-treated mice. sVEGFR-2 did not correlate with tumor volume in controls; mice treated with cediranib had lower relative VEGFR-2 plasma concentrations and tumor burdens. In conclusion, cediranib showed potent antitumor and antiangiogenic efficacy in the RENCA model. sVEGFR-2 plasma concentrations can act as a surrogate marker for antitumor activity of VEGFR signaling inhibitors

Bax directly induces release of cytochrome c from isolated mitochondria

Bax is a pro-apoptotic member of the Bcl-2 protein family that resides in the outer mitochondrial membrane. It is controversial whether Bax promotes cell death directly through its putative function as a channel protein versus indirectly by inhibiting cellular regulators of the cell death proteases (caspases). We show here that addition of submicromolar amounts of recombinant Bax protein to isolated mitochondria can induce cytochrome c (Cyt c) release, whereas a peptide representing the Bax BH3 domain was inactive. When placed into purified cytosol, neither mitochondria nor Bax individually induced proteolytic processing and activation of caspases. In contrast, the combination of Bax and mitochondria triggered release of Cyt c from mitochondria and induced caspase activation in cytosols. Supernatants from Bax-treated mitochondria also induced caspase processing and activation. Recombinant Bcl-X(L) protein abrogated Bax-induced release of Cyt c from isolated mitochondria and prevented caspase activation. In contrast, the broad-specificity caspase inhibitor benzyloxycarbonyl-valinyl-alaninyl-aspartyl-(0-methyl)-fluoromethylketone (zVAD-fmk) and the caspase-inhibiting protein X-IAP had no effect on Bax-induced release of Cyt c from mitochondria in vitro but prevented the subsequent activation of caspases in cytosolic extracts. Unlike Ca(2+), a classical inducer of mitochondrial permeability transition, Bax did not induce swelling of mitochondria in vitro. Because the organellar swelling caused by permeability transition causes outer membrane rupture, the findings, therefore, dissociate these two events, implying that Bax uses an alternative mechanism for triggering release of Cyt c from mitochondria

Erratum: Vascular endothelial growth factor C promotes ovarian carcinoma progression through paracrine and autocrine mechanisms (The American Journal of Pathology (2014) 184 (1050-1061))

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