A BH3 Mimetic for Killing Cancer Cells

Green, Douglas R.

doi:10.1016/j.cell.2016.05.080

Cited by 69 publications

(60 citation statements)

References 9 publications

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“…In 2016, venetoclax has been approved by the FDA for the treatment of 17p-deleted chronic lymphocytic leukemia [8,51].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, these cells, designated as Bcl-2-dependent cancer cells, are addicted to Bcl-2 for their survival despite high levels of pro-apoptotic proteins like the BH3-only protein Bim. Therefore, Bcl-2 antagonism has been shown to be a promising therapeutic avenue for these cancers [7,8]. An important class of Bcl-2 inhibitors are the BH3-mimetic drugs [9][10][11], including ABT-737 [12], its orally bioavailable derivative ABT-263 (navitoclax) [13] and ABT-199 (venetoclax) [14].…”

Section: Introductionmentioning

confidence: 99%

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The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

Vervloessem

Ivanova

Luyten

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In 2016, venetoclax has been approved by the FDA for the treatment of 17p-deleted chronic lymphocytic leukemia [8,51].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

Vervloessem

Ivanova

Luyten

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…These features of BH3-only proteins have driven the development of chemical and peptide BH3 mimetics to inhibit both cellular and viral Bcl-2 homologs for clinical applications (Oltersdorf et al, 2005; Petros et al, 2004). The anti-cancer therapeutic Venetoclax, which binds the BH3-binding groove of Bcl-2 to promote cell death, is the first of these to be FDA approved (Green, 2016). BH3 mimetics may have other potential uses.…”

Section: Many Events and Conditions Influence Mitochondrial Dynamicsmentioning

confidence: 99%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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“…ABT-199 has demonstrated effective in vitro and in vivo cell killing in a range of cancers, including chronic myelogenous leukemia (CML), AML, and T-cell ALL (79–81). Based on its efficacy in clinical studies, ABT-199 has recently gained FDA approval for the treatment of refractory 17-p-deleted CLL, making it the first clinically approved small molecule targeting intracellular protein:protein interactions (82). Interestingly, there are reports describing ABT-199 inducing cell death in normal immune cell subsets in addition to its desired anticancer activity as was found in the case of normal mature B cells isolated from patients with CLL (83).…”

Section: Bh3 Mimetics As Anticancer Therapeuticsmentioning

confidence: 99%

Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation

et al. 2016

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A crucial component of regulating organismal homeostasis is maintaining proper cell number and eliminating damaged or potentially malignant cells. Apoptosis, or programed cell death, is the mechanism responsible for this equilibrium. The intrinsic apoptotic pathway is also especially important in the development and maintenance of the immune system. Apoptosis is essential for proper positive and negative selection during B- and T-cell development and for efficient contraction of expanded lymphocytes following an immune response. Tight regulation of the apoptotic pathway is critical, as excessive cell death can lead to immunodeficiency while apoptotic resistance can lead to aberrant lymphoproliferation and autoimmune disease. Dysregulation of cell death is implicated in a wide range of hematological malignancies, and targeting various components of the apoptotic machinery in these cases is an attractive chemotherapeutic strategy. A wide array of compounds has been developed with the purpose of reactivating the intrinsic apoptotic pathway. These compounds, termed BH3 mimetics are garnering considerable attention as they gain greater clinical oncologic significance. As their use expands, it will be imperative to understand the effects these compounds have on immune homeostasis. Uncovering their potential immunomodulatory activity may allow for administration of BH3 mimetics for direct tumor cell killing as well as novel therapies for a wide range of immune-based directives. This review will summarize the major proteins involved in the intrinsic apoptotic pathway and define their roles in normal immune development and disease. Clinical and preclinical BH3 mimetics are described within the context of what is currently known about their ability to affect immune function. Prospects for future antitumor immune amplification and immune modulation are then proposed.

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A BH3 Mimetic for Killing Cancer Cells

Cited by 69 publications

References 9 publications

The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation

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