Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Zhao, Xiao‐Yun; Wang, Xiu-Yun; Wei, Qi-Yao; Xu, Yan‐Ming; Lau, Andy T. Y.

doi:10.3390/cells9041012

Cited by 35 publications

(29 citation statements)

References 154 publications

(146 reference statements)

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“…When cells are stimulated by apoptosis, mitochondria release Smac protein into the cytoplasm to bind to IAPs, making it lose the inhibition of caspase activity and subsequently promote cell apoptosis. 11 , 20 , 34 Three previous papers published in Cell 35 , 36 , 37 have reported that Smac mimetics can induce auto‐ubiquitination and cIAP1/2 degradation through different mechanisms, leading to tumour necrosis‐factor‐alpha‐mediated cancer cell death. 38 These studies have prompted the introduction of Smac mimetics in anti‐cancer therapies.…”

Section: Discussionmentioning

confidence: 99%

cIAP1/2 are involved in the radiosensitizing effect of birinapant on NSCLC cell line in vitro

Sun

Yao

et al. 2021

J Cellular Molecular Medi

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Tumour radioresistance is a major problem for cancer radiation therapy. To identify the underlying mechanisms of this resistance, we used human non‐small cell lung cancer (NSCLC) cell lines and focused on the Inhibitor of Apoptosis Protein (IAP) family, which contributes to tumourigenesis and chemoresistance. We investigated the possible correlation between radioresistance in six NSCLC cell lines and IAP protein levels and tested the radiosensitizing effect of birinapant in vitro, a molecule that mimics the second mitochondria‐derived activator of caspase. We found that birinapant‐induced apoptosis and inhibited the proliferation of NSCLC cells after exposure to radiation. These effects were induced by birinapant downregulation of cIAP protein levels and changes of cIAP gene expression. Overall, birinapant can inhibit tumour growth of NSCLC cell lines to ironizing radiation and act as a promising strategy to overcome radioresistance in NSCLC.

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Section: Discussionmentioning

confidence: 99%

cIAP1/2 are involved in the radiosensitizing effect of birinapant on NSCLC cell line in vitro

Sun

Yao

et al. 2021

J Cellular Molecular Medi

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“…In addition to augmenting SMAC mimetic-induced apoptosis, TNF-α could have broader effects on the immune system by stimulating cytotoxic T cells to act against cancer cells [ 36 ]. Previous work supported testing birinapant in combination with immune checkpoint inhibitors [ 5 , 37 , 38 ]. Our new findings suggested that the addition of docetaxel could further sensitize cancer cells to treatment with SMAC mimetics and immune checkpoint inhibitors, which is currently under active investigation.…”

Section: Discussionmentioning

confidence: 99%

“…To prevent inappropriate activation of these pathways, cell death is strictly regulated by both pro-apoptotic and anti-apoptotic proteins. Inhibitor of apoptosis (IAP) proteins are one such regulator that block executioner caspase function [ 5 ]. Second mitochondrial activator of caspases (SMAC) proteins, on the other hand, antagonize IAP proteins, thereby promoting cell death.…”

Section: Introductionmentioning

confidence: 99%

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

Noonan

Cousins

Anderson

et al. 2020

Cancers

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Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

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“…Smac release from mitochondria [138]. Increase tumor cells sensitivity to granzyme-induced apoptosis.…”

Section: Radiation-induced Effectmentioning

confidence: 99%

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment

Tubin

Gupta

Jeremić

2021

Cancers

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The overall prognosis and survival of non-small cell lung cancer (NSCLC) patients remain poor. The immune system plays an integral role in driving tumor control, tumor progression, and overall survival of NSCLC patients. While the tumor cells possess many ways to escape the immune system, conventional radiotherapy (RT) approaches, which are directly cytotoxic to tumors, can further add additional immune suppression to the tumor microenvironment by destroying many of the lymphocytes that circulate within the irradiated tumor environment. Thus, the current immunogenic balance, determined by the tumor- and radiation-inhibitory effects is significantly shifted towards immunosuppression, leading to poor clinical outcomes. However, newer emerging evidence suggests that tumor immunosuppression is an “elastic process” that can be manipulated and converted back into an immunostimulant environment that can actually improve patient outcome. In this review we will discuss the natural immunosuppressive effects of NSCLC cells and conventional RT approaches, and then shift the focus on immunomodulation through novel, emerging immuno- and RT approaches that promise to generate immunostimulatory effects to enhance tumor control and patient outcome. We further describe some of the mechanisms by which these newer approaches are thought to be working and set the stage for future trials and additional preclinical work.

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Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

Cited by 35 publications

References 154 publications

cIAP1/2 are involved in the radiosensitizing effect of birinapant on NSCLC cell line in vitro

cIAP1/2 are involved in the radiosensitizing effect of birinapant on NSCLC cell line in vitro

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment

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