Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

https://www.sbmicrobiologia.org.br/PDF/industrial.pdf

Glycerol: A promising and abundant carbon source for industrial microbiology

The Sp/KLF family contains at least twenty identified members which include Sp1-4 and numerous kruppel-like factors. Members of the family bind with varying affinities to sequences designated as ‘Sp1 sites’ (e.g., GC-boxes, CACCC-boxes, and basic transcription elements). Family members have different transcriptional properties and can modulate each other's activity by a variety of mechanisms. Since cells can express multiple family members, Sp/KLF factors are likely to make up a transcriptional network through which gene expression can be fine-tuned. ‘Sp1 site’-dependent transcription can be growth-regulated, and the activity, expression, and/or post-translational modification of multiple family members is altered with cell growth. Furthermore, Sp/KLF factors are involved in many growth-related signal transduction pathways and their overexpression can have positive or negative effects on proliferation. In addition to growth control, Sp/KLF factors have been implicated in apoptosis and angiogenesis; thus, the family is involved in several aspects of tumorigenesis. Consistent with a role in cancer, Sp/KLF factors interact with oncogenes and tumor suppressors, they can be oncogenic themselves, and altered expression of family members has been detected in tumors. Effects of changes in Sp/KLF factors are context-dependent and can appear contradictory. Since these factors act within a network, this diversity of effects may arise from differences in the expression profile of family members in various cells. Thus, it is likely that the properties of the overall network of Sp/KLF factors play a determining role in regulation of cell growth and tumor progression. © 2001 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.1111

Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer

For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.

Targeting apoptosis in cancer therapy

. Since discovery over a decade ago of a role for the cytokine TGF-s as key mediator of glomerular and tubulointerstitial pathobiology in chronic kidney diseases, studies of TGF-s signaling in the kidney have focused on the molecular biology of fibrogenesis. In recent years, glomerular and tubular epithelial cell apoptosis and cellular transdifferentiation have been proposed as putative primary pathomechanisms that may underlie progression of renal disease. This review describes evidence in support of nonlinear models and functional roles of TGF-s signaling in mediating apoptosis and epithelial-to-mesenchymal transdifferentiation (EMT) in chronic progressive renal disease. Emphasis is placed on cell context-dependent models of TGF-s signaling providing a conceptual framework to consolidate seemingly distinct pathomechanisms of progression of glomerular and tubulointerstitial disease.E-mail: bottinge@aecom.yu.edu

TGF-β signaling in renal disease

MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells

Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells.

In Vitro Evaluation of Fludarabine in Combination With Cyclophosphamide and/or Mitoxantrone in B-Cell Chronic Lymphocytic Leukemia

Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2800%2901922-0

Gabriel Pons

Papers

MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells

Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells.

In Vitro Evaluation of Fludarabine in Combination With Cyclophosphamide and/or Mitoxantrone in B-Cell Chronic Lymphocytic Leukemia

Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells

Aspirin induces apoptosis through mitochondrial cytochrome c release.