Several studies are now focused on the identification of expression signatures that could be used to predict sensitivity to the BCL-2 inhibitors and allow the identification of subgroups of patients that would benefit more from more selective or more promiscuous inhibitors
Several studies are now focused on the identification of expression signatures that could be used to predict sensitivity to the BCL-2 inhibitors and allow the identification of subgroups of patients that would benefit more from more selective or more promiscuous inhibitors. Acknowledgements DENDRIX assisted with the preparation of the manuscript. AbbVie participated in the interpretation of data, review, and approval of the content. Funding AbbVie funded medical writing services provided by Ana Elisa Barreiros Bueno da Silva, a DENDRIX employee. Abbreviations ALLAcute lymphoblastic leukemiaAMLAcute myelogenous leukemiaBCL-2B-cell lymphoma-2BCRiB-cell receptor pathway inhibitorBHBCL-2 homology domainBPDCNBlastic plasmacytoid dendritic cell neoplasmCBCLCutaneous B-cell lymphomaCLLChronic lymphocytic leukemiaCRComplete responseDLBCLDiffuse large B-cell lymphomaMMMultiple myelomaMOMPMytochondria AZD5438 outer membrane permeabilizationNHLNon-Hodgkin lymphomaORROverall response ratePFSProgression free survivalR/RRelapsed/refractorySLLSmall lymphocytic lymphomaVGPRVery good partial response Authors contributions All authors designed, drafted, discussed, and revised the manuscript. with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. This review focuses on the relevance of BCL-2 for apoptosis modulation at the mitochondrial AZD5438 level, its potential as therapeutic target for hematological malignancies, and the results obtained with selective inhibitors belonging to the BH3-mimetics, especially venetoclax used in monotherapy or in combination with other agents. was the first gene shown to promote prolonged cell survival rather than increased proliferation [4, 7]. This discovery led to the concept that inhibition of apoptosis is an important step in tumorigenesis . Promising results are being reported with the use of inhibitors of BCL-2 and other related molecules, especially with BH3-mimetics [8, 9]. Given that apoptosis blockage is a key oncogenic mechanism in lymphoid malignancies, and that BCL-2 overexpression is a common finding in leukemias and lymphomas, many antagonists of anti-apoptotic BCL-2 have been developed and investigated for the treatment of hematological neoplasms [2, 6]. BH3-mimetics comprise a novel class of BCL-2 inhibitors that have shown promising results in several hematological malignancies, both as single agents and in combination with AZD5438 other anti-cancer drugs. Among the BH3-mimetics, venetoclax (also known as ABT-199), a potent and selective inhibitor of BCL-2, was recently approved by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) with 17p deletion based on its favorable safety profile and high response rates . Here, we review the role of BCL-2 protein on apoptosis regulation, its importance as therapeutic target for hematological malignancies and the results obtained with BH3-mimetics drugs on preclinical and clinical trials. The apoptosis machinery Apoptosis is a highly complex and well-regulated form of programmed cell death. It plays an essential role in embryogenesis, tissue development, immunity, and maintenance of homeostasis. However, both excessive and insufficient cell death can lead to a wide variety of pathological conditions including neurodegenerative diseases, immunological disorders, and cancer [11C13]. In the hematopoietic system, programmed cell death exerts an important role, allowing cell turnover and rapid expansion and retraction of cell populations in response to infection . Caspase activation plays a crucial role in apoptosis, with caspases being known as the central executioners of the apoptotic machinery. The proteolytic events mediated by caspases result in peculiar morphological and ultrastructural changes in dying cell that, ultimately, define the apoptotic phenotype . Upon activation, caspases can often cleave and activate other procaspases, initiating a proteolytic cascade. In addition, some procaspases are also capable to form aggregates and undergo autoactivation. This proteolytic cascade, in which one caspase can activate other caspases, and in some cases, activate themselves, allows the amplification of signaling that leads to cell death . Two major pathways for caspase activation and apoptosis initiation have been described in vertebrates: the extrinsic pathway and the intrinsic pathway. The extrinsic pathway involves the activation of cell death receptors located on the cell surface, such as tumor necrosis factor receptors or Fas, and whose interaction to their ligands promote the activation of caspase-8. In the intrinsic pathway, also known as the AZD5438 mitochondrial pathway, disruption of mitochondrial integrity is the crucial decision point . Mitochondria outer membrane permeabilization (MOMP) allows C13orf15 proteins located in the intermembrane space of the mitochondria to be released into the cytosol, thus triggering apoptosis . Both intrinsic and extrinsic pathways culminate on the activation of a caspase cascade that will activate the signaling route leading to the morphological features that characterize apoptotic cells. Cell shrinkage, plasma membrane blebbing with no loss of integrity, DNA fragmentation, and condensation of chromatin are among the characteristics exhibited by cells going through apoptosis. This culminates with the forming of apoptotic systems and their following speedy removal by phagocytosis AZD5438 and degradation by various other encircling cells [11, 16]. The apoptotic phenotype is normally elicited with the cleavage of mobile substrates by caspases, activated caspase-3  especially. Apoptosis could be triggered by a number of pathologic and physiologic stimuli. The mitochondrial pathway is normally turned on by different types of mobile stress, such as for example DNA loss and damage of survival alerts . It’s the apoptotic pathway turned on by many cytokine deprivation also, chemical substances, and by healing agents, including cancers chemotherapeutic irradiation and medications . The mitochondria enjoy a central function in apoptosis legislation even though caspases are known as the executioners of apoptosis, the BCL-2 family are referred to as the regulators,.