Abstract
Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy-refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action—direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.
Highlights
Caspase-dependent apoptosis represents the most flexible and widely used regulated cell death (RCD) modality utilized in the animal kingdom by both invertebrates and vertebrates during embryonic development as well as in adult organisms with rapid and effective efferocytosis of dead cells [1]
The B-cell lymphoma 2 (BCL2) family of proteins contains 1–4 evolutionary-conserved BCL2 homology (BH) domains and can, in respect to cell survival, be formally divided into two groups— a/inducing/enhancing or b/suppressing intrinsic/mitochondria-linked apoptosis. The former can be further subdivided into two groups—multidomain effectors of the intrinsic apoptosis BCL2 associated X (BAX), BCL2 antagonist/killer 1 (BAK1), and BOK and BCL2 homology 3 (BH3)-only sentinels/activators/, which transduce a pro-apoptotic stress signal to the multidomain BCL2 family proteins (Figure 1) [8]
Multidomain BCL2 family proteins contain, in addition to BH domains, a C-terminal transmembrane domain (TM) allowing them to associate with intracellular membranes such as the mitochondrial outer membrane (MOM), endoplasmic reticulum (ER), and nuclear membranes [11]
Summary
Caspase-dependent apoptosis represents the most flexible and widely used regulated cell death (RCD) modality utilized in the animal kingdom by both invertebrates and vertebrates during embryonic development as well as in adult organisms with rapid and effective efferocytosis of dead cells [1]. Apoptotic signaling in mammalian cells can be triggered by exogenous/extrinsic stimuli such as death/dependence receptors or cytotoxic perforin/granzymes-containing granules and by a range of intrinsic stimuli. The majority of current anti-cancer drugs represent effective indirect activators of intrinsic mitochondria-dependent apoptotic signaling. The efficient triggering of either apoptotic signaling pathway relies on pronounced activation of the initiator caspases-8 and/or -9 in respective multiprotein complexes—the death-inducing signaling complex (caspase-8) and apoptosome (caspase-9) [2]. Caspase-dependent apoptosis represents the predominant non-inflammatory RCD mode triggered in the majority of hematologic and other malignancies [5]. Apoptotic blocks that prevent cancer cells from initiating programmed cell death in response to various pro-apoptotic stimuli represents one of the recognized hallmarks of cancer [6,7]
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