SMAC mimetics in combination with the pro-inflammatory cytokine TNFα augment cell death in B-13 progenitor-derived hepatocytes

Abstract Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.

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Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

Cell Death and Differentiation ◽

10.1038/s41418-019-0441-3 ◽

2019 ◽

Vol 27 (5) ◽

pp. 1569-1587 ◽

Cited By ~ 2

Author(s):

Jing Zhang ◽

Yu Yang ◽

Shen’ao Zhou ◽

Xueyan He ◽

Xuan Cao ◽

...

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cancer Cell ◽

Tumor Regression ◽

Cell Types ◽

Tight Contact ◽

Cancer Cell Death ◽

Microtubule Targeting Agents ◽

Patient Responsiveness ◽

Smac Mimetics

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

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The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Cells ◽

10.3390/cells9010207 ◽

2020 ◽

Vol 9 (1) ◽

pp. 207 ◽

Cited By ~ 3

Author(s):

Jessica Michie ◽

Conor J. Kearney ◽

Edwin D. Hawkins ◽

John Silke ◽

Jane Oliaro

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Tumour Progression ◽

Mitochondrial Protein ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Inhibitor Of Apoptosis ◽

T Cell Therapy ◽

Apoptosis Protein ◽

Smac Mimetics

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

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Future Therapeutic Directions for Smac-Mimetics

Cells ◽

10.3390/cells9020406 ◽

2020 ◽

Vol 9 (2) ◽

pp. 406 ◽

Cited By ~ 10

Author(s):

Emma Morrish ◽

Gabriela Brumatti ◽

John Silke

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Tumor Growth ◽

Cancer Cells ◽

Inhibitor Of Apoptosis ◽

Growth Strategies ◽

Promote Tumor Growth ◽

Cell Death Program ◽

Smac Mimetics ◽

Promote Cell Death

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

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TWEAKing death

The Journal of Cell Biology ◽

10.1083/jcb.200806036 ◽

2008 ◽

Vol 182 (1) ◽

pp. 15-17 ◽

Cited By ~ 6

Author(s):

Jonathan D. Ashwell

Keyword(s):

Cell Death ◽

Cell Biology ◽

Nuclear Factor Κb ◽

Tnf Receptor ◽

Tumor Cell Death ◽

Cell Death Pathways ◽

Tnf Α ◽

Selective Elimination ◽

Smac Mimetics ◽

Necrosis Factor

Smac mimetics (inhibitor of apoptosis [IAP] antagonists) are synthetic reagents that kill susceptible tumor cells by inducing degradation of cellular IAP (cIAP) 1 and cIAP2, nuclear factor κB activation, tumor necrosis factor (TNF) α production, TNF receptor 1 occupancy, and caspase-8 activation. In this issue of The Journal of Cell Biology, Vince et al. (see p. 171) report remarkable similarities in the events leading to tumor cell death triggered by the cytokine TWEAK (TNF-like weak inducer of apoptosis) and IAP antagonists. Although the mechanistic details differ, a common and necessary feature that is also shared by TNF receptor 2 signaling is reduction in the level of cIAP1 and, in some cases, cIAP2 and TNF receptor-associated factor 2. These findings not only extend our appreciation of how cell death pathways are kept in check in tumors, they reinforce the possible utility of induced cIDE (cIAP deficiency) in the selective elimination of neoplastic cells.

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Hyperalgesia induced by oral stavudine administration to rats does not depend on spinal neuronal cell death, or on spinal or systemic inflammatory cytokine secretion, or metabolic dysregulation

NeuroToxicology ◽

10.1016/j.neuro.2009.02.007 ◽

2009 ◽

Vol 30 (3) ◽

pp. 423-429

Author(s):

Juliane Weber ◽

Duncan Mitchell ◽

Demetri Veliotes ◽

Bridget Mitchell ◽

Peter R. Kamerman

Keyword(s):

Cell Death ◽

Inflammatory Cytokine ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cytokine Secretion ◽

Metabolic Dysregulation

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Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity

Cell Death and Disease ◽

10.1038/cddis.2013.449 ◽

2013 ◽

Vol 4 (11) ◽

pp. e920-e920 ◽

Cited By ~ 26

Author(s):

D Lecis ◽

M De Cesare ◽

P Perego ◽

A Conti ◽

E Corna ◽

...

Keyword(s):

Cell Death ◽

Tumour Cell ◽

Macrophage Activity ◽

Smac Mimetics ◽

Tumour Cell Death ◽

Necrotic Tumour

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IGF2: an endocrine hormone to improve islet transplant survival

Journal of Endocrinology ◽

10.1530/joe-13-0557 ◽

2014 ◽

Vol 221 (2) ◽

pp. R41-R48 ◽

Cited By ~ 10

Author(s):

Amy Hughes ◽

Darling Rojas-Canales ◽

Chris Drogemuller ◽

Nicolas H Voelcker ◽

Shane T Grey ◽

...

Keyword(s):

Cell Death ◽

Islet Transplantation ◽

Inflammatory Cytokine ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Pancreatic Islet Transplantation ◽

Post Transplant ◽

Islet Transplant ◽

Clinical Islet Transplantation ◽

Islet Survival

In the week following pancreatic islet transplantation, up to 50% of transplanted islets are lost due to apoptotic cell death triggered by hypoxic and pro-inflammatory cytokine-mediated cell stress. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve islet transplant success. IGF2 is an anti-apoptotic endocrine protein that inhibits apoptotic cell death through the mitochondrial (intrinsic pathway) or via antagonising activation of pro-inflammatory cytokine signalling (extrinsic pathway), in doing so IGF2 has emerged as a promising therapeutic molecule to improve islet survival in the immediate post-transplant period. The development of novel biomaterials coated with IGF2 is a promising strategy to achieve this. This review examines the mechanisms mediating islet cell apoptosis in the peri- and post-transplant period and aims to identify the utility of IGF2 to promote islet survival and enhance long-term insulin independence rates within the setting of clinical islet transplantation.

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Cuprizone Affects Hypothermia-Induced Neuroprotection and Enhanced Neuroblast Differentiation in the Gerbil Hippocampus after Ischemia

Cells ◽

10.3390/cells9061438 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1438

Author(s):

Woosuk Kim ◽

Kyu Ri Hahn ◽

Hyo Young Jung ◽

Hyun Jung Kwon ◽

Sung Min Nam ◽

...

Keyword(s):

Cell Death ◽

Dentate Gyrus ◽

Neuronal Plasticity ◽

Inflammatory Cytokine ◽

Proliferating Cells ◽

Reactive Microglia ◽

Neuroblast Differentiation ◽

Cytokine Levels ◽

Ad Libitum ◽

Pro Inflammatory Cytokines

In the present study, we investigated the effects of cuprizone on cell death, glial activation, and neuronal plasticity induced by hypothermia after ischemia in gerbils. Food was supplemented with cuprizone at 0.2% ad libitum for eight weeks. At six weeks after diet feeing, gerbils received transient forebrain ischemia with or without hypothermic preconditioning. Cuprizone treatment for 8 weeks increased the number of astrocytes, microglia, and pro-inflammatory cytokine levels in the hippocampus. In addition, cuprizone treatment significantly decreased the number of proliferating cells and neuroblasts in the dentate gyrus. Brain ischemia caused cell death, disruption of myelin basic proteins, and reactive gliosis in CA1. In addition, ischemia significantly increased pro-inflammatory cytokines and the number of proliferating cells and differentiating neuroblasts in the dentate gyrus. In contrast, hypothermic conditioning attenuated these changes in CA1 and the dentate gyrus. However, cuprizone treatment decreased cell survival induced by hypothermic preconditioning after ischemia and increased the number of reactive microglia and astrocytes in CA1 as well as that of macrophages in the subcallosal zone. These changes occurred because the protective effect of hypothermia in ischemic damage was disrupted by cuprizone administration. Furthermore, cuprizone decreased ischemia-induced proliferating cells and neuroblasts in the dentate gyrus.

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