XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

Tian, Xiaohong; Hou, Wei; Bai, Shuling; Fan, Jun; Tu, Hao; Bai, Yu

doi:10.3892/or.2014.3460

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…Our data are consistent with Tnks inhibitorinduced telomeric shortening independent of changes to the Wnt signaling status in this cell line. We note that another study using XAV-939 observed similar effects on telomere length maintenance in a neuroblastoma cell line, thereby extending the relevance of our findings to other cell types (35). Taken together, our findings reveal a single-agent strategy for inducing telomerase shortening that is distinct from current efforts devoted to directly targeting telomerase.…”

Section: Resultsmentioning

confidence: 46%

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Kulak

Chen

Holohan

et al. 2015

Molecular and Cellular Biology

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Section: Resultsmentioning

confidence: 46%

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Kulak

Chen

Holohan

et al. 2015

Molecular and Cellular Biology

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“…XAV939 is an inhibitor of tankyrase, a positive regulator or telomerase. It has been shown to induce apoptosis in the telomerase expressing neuroblastoma cell line SH-SY5Y [70].…”

Section: Drugs Targeting Telomerase Activitymentioning

confidence: 99%

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

George

Parmar

Lorenzi

et al. 2020

J Exp Clin Cancer Res

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The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease. Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2′-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted. In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

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“…Also, tankyrase 1/2 inhibitors such as XAV935 and XAV939 may have promising effects in progressed and chemoresistant relapsed NB. They were reported to increase apoptosis by the induction of telomere shortening, prevent chemoresistance and inhibit WNT-β-catenin signaling, even in MYCN-amplified tumors [70,71,104,105]. However, NB is a tumor of children and most cases occur in young children.…”

Section: Are Wnt Pathways Druggable In Nb?mentioning

confidence: 99%

WNT Signaling in Neuroblastoma

Becker

Wilting

2019

Cancers

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The term WNT (wingless-type MMTV integration site family) signaling comprises a complex molecular pathway consisting of ligands, receptors, coreceptors, signal transducers and transcriptional modulators with crucial functions during embryonic development, including all aspects of proliferation, morphogenesis and differentiation. Its involvement in cancer biology is well documented. Even though WNT signaling has been divided into mainly three distinct branches in the past, increasing evidence shows that some molecular hubs can act in various branches by exchanging interaction partners. Here we discuss developmental and clinical aspects of WNT signaling in neuroblastoma (NB), an embryonic tumor with an extremely broad clinical spectrum, ranging from spontaneous differentiation to fatal outcome. We discuss implications of WNT molecules in NB onset, progression, and relapse due to chemoresistance. In the light of the still too high number of NB deaths, new pathways must be considered.

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XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

Cited by 14 publications

References 35 publications

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

WNT Signaling in Neuroblastoma

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