Special Issue "Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 February 2020).

Special Issue Editor

Prof. Zhong Chen
Website
Guest Editor
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20814, USA
Interests: cancer genomic; cellular biology; signal pathway; animal models; head and neck cancer

Special Issue Information

Dear Colleagues,

The major hallmarks of cancer development involve a cascade of events including loss of control for cell death, induced by the interruption of extrinsic and intrinsic apoptotic pathways, such as TP53, caspases, TNF, TNF-related apoptosis-inducing ligand (TRAIL), and inhibitor of apoptosis proteins (IAPs). Recently, The Cancer Genome Atlas (TCGA) revealed genomic and expression alterations of various components in the death pathway in many malignancies, such as TP53 and caspase mutations, the deletion of TRAIL receptors, and amplification and overexpression of the Fas-associated via death domain (FADD) and IAPs. These molecules and complexes are critical in cell death, survival, and drug resistance. The IAP molecules are defined by the presence of Baculoviral IAP Repeat (BIR) domains, which mediate protein–protein interactions. The major IAP family proteins in mammalian include c-IAP1, c-IAP2, and XIAP, which function as endogenous inhibitors of caspases involved in both intrinsic and extrinsic pathways. A strong endogenous antagonist of IAP proteins has been identified in the intrinsic death pathway, which is a mitochondrial protein known as a second mitochondria-derived activator of caspases (SMAC). When SMAC is released from the mitochondria, it binds to IAPs, relieves the inhibition of caspases, and leads to the apoptotic cascade. SMAC mimetic or synthetic IAP antagonist therapy has been developed as the major strategy to inhibit IAPs and induce cell death in cancer preclinical models and patients. The optimal activity of SMAC mimetics therapy has been observed in the combination with the death signals, such as TNF, TRAIL, and FasL. In addition, there are non-SMAC mimetic IAP antagonists used as the therapeutic agents in clinical trials. Most drugs targeting IAPs are still in early phase clinical trials. 

This Special Issue will cover the results of original studies and review articles using preclinical animal or cell culture models to investigate the mechanisms of IAP inhibitors on cancers; the bioinformatics and protein structure analysis of the interaction of IAP proteins and other death molecules; the drug target effects related to the cancer genomic or expression alterations of the molecules involved in the extrinsic and intrinsic death pathways; the network cross-talk among TP53, IAPs, TNF, TRAIL, and other death pathways; regulation of innate and adaptive antitumor immunity by IAP inhibitors; the genomic and molecular biomarkers predicting the efficacy of IAP inhibitors in clinical trials; a combination of IAP inhibitors and conventional chemo- and radiation therapies; as well as the current status and development of new small or large molecules targeting IAP and related death pathways. 

Prof. Zhong Chen
Guest Editor

Manuscript Submission Information

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Keywords

  • inhibitor of apoptosis proteins (IAPs)
  • IAP antagonist
  • SMAC mimetic
  • extrinsic and intrinsic death pathways
  • cancer
  • biomarkers
  • pre-clinical studies
  • clinical trials

Published Papers (3 papers)

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Review

Open AccessReview
Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC
Cells 2020, 9(3), 663; https://doi.org/10.3390/cells9030663 - 09 Mar 2020
Abstract
Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the [...] Read more.
Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP. Full article
(This article belongs to the Special Issue Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy)
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Open AccessReview
Future Therapeutic Directions for Smac-Mimetics
Cells 2020, 9(2), 406; https://doi.org/10.3390/cells9020406 - 11 Feb 2020
Abstract
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy)
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Open AccessReview
The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy
Cells 2020, 9(1), 207; https://doi.org/10.3390/cells9010207 - 14 Jan 2020
Cited by 2
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Inhibitor of Apoptosis Proteins (IAPs) in Cancer Therapy)
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