AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells

Lü, Jing; Qin, Qin; Li, Zhan; Liu, Jia; Zhu, Hongcheng; Yang, Xi; Zhang, Chi; Xu, Liping; Liu, Zheming; Wang, Di; Cui, He-Qing; Meng, Ciu-Ciu; Cai, Jing; Cheng, Hongyan; Sun, Xinchen

doi:10.1254/jphs.14079fp

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…Our findings are consistent with those of Lu et al on the Smac mimetic AT‐406 in cervical cancer. They showed that upon AT‐406 treatment, cells were more sensitive to radiation in hypoxia than in normoxia and that cIAP1 and XIAP degradation was increased in hypoxia . These results support the implication of a direct endogenous IAP protein antagonist that could be downregulated in hypoxia similarly to Smac or deubiquitinases .…”

Section: Discussionmentioning

confidence: 74%

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

et al. 2019

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In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor‐κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem‐like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC‐0152, a small‐molecule IAPs inhibitor, triggered stem‐like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three‐dimensional glioblastoma spheroid model in which time‐of‐flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein+ cells at their periphery. These oxygen‐dependent GDC‐0152 antitumoral effects have been confirmed on human glioblastoma explants. Notably, serine–threonine kinase activation analysis revealed that under hypoxic conditions, IAP inhibition activated ataxia telangiectasia and Rad3‐related protein signaling. Our findings provide new insights into the dual mechanism of action of IAP inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019;37:731–742

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Section: Discussionmentioning

confidence: 74%

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

et al. 2019

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“…Limited anti-tumour activity may suggest development rather as adjunct treatment [ 16 ]. AT-406 acts as a strong radio sensitizer in human cervical cancer cells [ 17 ] and has demonstrated anti-ovarian cancer efficacy as a single agent and in combination with carboplatin [ 18 ]. In addition, AT-406 is highly effective in induction of apoptosis in xenograft tumours and is currently in phase I clinical trials for the treatment of of solid and hematological human tumors [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis

et al. 2016

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BackgroundHigh expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs.MethodsIn this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols.ResultsIt is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability, migration and can very efficiently sensitize colorectal tumour cells to apoptosis. Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically, as shown by median effect analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression.ConclusionsProposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo, from precision tumour biology to precision medical oncology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2606-5) contains supplementary material, which is available to authorized users.

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“…Our findings are consistent with those of Lu et al on the Smac mimetic AT-406 in cervical cancer. They showed that upon AT-406 treatment, cells were more sensitive to radiation in hypoxia than in normoxia and that cIAP1 and XIAP degradation was increased in hypoxia (Lu et al, 2014). These results support the implication of a direct endogen IAP protein antagonist which could be down-regulated in hypoxia similarly to Smac or deubiquitinases (Guo et al, 2014;Lee & Song, 2015;Engel et al, 2016).…”

Section: Discussionmentioning

confidence: 72%

Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level

Soubéran

Cappaï

Chocry

et al. 2018

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Abstract:In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and non-apoptotic processes. Here we used GDC-0152, a small molecule IAP inhibitor, to explore how IAPs participate in glioblastoma stem-like cell maintenance and fate under both hypoxic and normoxic environments. In hypoxia, IAPs inhibition triggered stem-like cells apoptosis and decreased proliferation in four human glioblastoma cell lines, whereas in normoxia it induced a loss of stemness and differentiation. In addition, we characterized a 3D glioblastoma spheroid model. By using MALDI images we validated that GDC-0152 penetrates in the entire sphere. TOF-SIMS analyses revealed an oxygen gradient correlated with spatial cellular heterogeneity with proliferative and apoptotic cells located close to the hypoxic core and GFAP + cells at the periphery. Notably, Serine-Threonine Kinases activation analysis revealed that oxygen level affects signaling pathways activated by GDC-0152. In hypoxia, IAPs inhibition activated ATR whereas in normoxia it activated NF-κB. Our data brings new mechanistic insights revealing the dual role of IAPs inhibitors like GDC-0152 that are relevant to their therapeutic application in tumors like glioblastomas. Running title: IAPs determine glioblastoma cells fate

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AT-406, an IAP Inhibitor, Activates Apoptosis and Induces Radiosensitization of Normoxic and Hypoxic Cervical Cancer Cells

Cited by 12 publications

References 35 publications

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis

Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level

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