Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Chen, Zhenghu; Wang, Long; Yao, Dayong; Yang, Tianshu; Cao, Wen; Dou, Jun; Pang, Ji‐Jie; Guan, Shan; Zhang, Huiyuan; Ye, Yu; Zhao, Yanling; Wang, Yongfeng; Xu, Xin; Shi, Yan; Patel, Roma H.; Zhang, Hong; Vasudevan, Sanjeev A.; Liu, Shangfeng; Yang, Jianhua; Nuchtern, Jed G.

doi:10.1038/srep38011

Cited by 31 publications

(28 citation statements)

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“…Expression of proteins including CHEK1, CHEK2, ERCC1, ERCC2, PARP and WEE1 predispose cancer cells treated with chemotherapy toward DNA repair and proliferation. As such, these proteins have been identified as either prognostic biomarkers or therapeutic targets to improve chemotherapeutic effects in pediatric tumors [122][123][124][125][126][127][128][129][130][131][132] . The mechanisms that balance the expression and stability of these proteins continue to be areas of active investigation.…”

Section: Dna Damage Pathwaysmentioning

confidence: 99%

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Shah¹

2019

CDR

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While advances in the treatment of pediatric cancers have improved survival to > 80% across all tumor types, drug resistance continues to limit survival for a considerable number of patients. We review the known mechanisms of resistance in pediatric cancers, including processes that impair conventional chemotherapies, newer classes of targeted small molecule antineoplastic drugs, and monoclonal antibodies. We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers. We also discuss newer areas of research into drug resistance, including extracellular and immune factors.

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Section: Dna Damage Pathwaysmentioning

confidence: 99%

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Shah¹

2019

CDR

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“…TP53 aracılı hücre ölüm yolağı-nın negatif bir düzenleyicisi olan PPM1D'nin inhibisyonu, CHK2/ TP53 aracılığıyla apoptozu indüklemek için yeni bir yaklaşım olarak öneril-miştir. 73 TP53 sinyal yolağının aşağı akışında bulunan nöroblastom hücrelerinde apoptozu indükleyen yeni tanımlanan proapoptotik BEX genleri yeni tümör baskılayıcılar olarak umut vadetmektedir. 74 EGFR'nin inhibisyonu, PI3K/ AKT/mTOR sinyal yolunun baskılanması yoluyla nöroblastom hücrelerini apoptoza yönlendir-mektedir.…”

Section: Hedefe Yöneli̇k Tedavi̇ Yaklaşimi Ve Gelecek Perspekti̇flerunclassified

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

Bağca¹,

Avcı²

2017

Turkiye Klinikleri J Neur

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Ö ÖZ ZE ET T Nöroblastom, embriyonik dönemde ortaya çıkan, nöral krest kaynaklı nadir bir kanser tü-rüdür. Santral sinir sistemindeki herhangi bir bölgeden ama sıklıkla böbrek üstü bezlerinden köken almaktadır. Hastalarda genellikle lenf düğümlerine, kemik iliğine ve kemiğe metastaz gerçekleş-mesi sağkalımı olumsuz şekilde etkilemektedir. Nöroblastomun başlangıçta tamamen ailesel bir hastalık olduğu düşünülse de ailesel olanlar tüm hastaların küçük bir bölümünü oluşturmaktadır. Nöroblastom patogenezinde rol aldığı tanımlanmış olan belli başlı mutasyonlar MYCN, ALK, PHOX2B, ATRX ve TERT genlerini içermektedir. Bununla birlikte artık sadece genetik değil epigenetik düzenlenim hatalarının da diğer pek çok hastalıkta olduğu gibi, nöroblastom patogenezinde görev aldığı bilinmektedir. Kromatin yapının regülasyonunu sağlayan histon modifikasyonları, gen ifadesinin kontrolünde görev alan DNA metilasyonu ve ncRNA'lar aracılığıyla gerçekleşen bu düzenlemelerin nöroblastomla ilişkisi araştırılmaktadır. Konvansiyonel tedavi, hastaların prognostik özelliklerine bağlı olarak cerrahi müdahale ile tümörün çıkarılması, kemoterapi, otolog kök hücre nakli ve radyoterapi yaklaşımlarını içermesine rağmen, kemoterapötiklere karşı direnç gelişimi ya da duyarsızlık sorunları sıklıkla ortaya çıkmaktadır. Bu sorunların üste-sinden gelmek, sağkalımı ve yaşam kalitesini artırmak için güncel tedavi yaklaşımları, doğrudan kanser hücresini elimine etmeyi amaçlayan "hedefe yönelik tedavi" yaklaşımlarının geliştirilme-sine odaklanmış durumdadır. Bu çalışmada, nöroblastom genetiği ve epigenetiği hakkında bildiklerimizin ve hedefe yönelik tedavi yaklaşımlarında nerede olduğumuzun güncel literatür verileri ile ortaya konulması amaçlanmıştır.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Nöroblastom; genetik; neoplastik kök hücreler; moleküler hedefe yönelik tedavi A AB BS S T TR RA AC CT T Neuroblastoma is a rare cancer arising in the embryonic stage, originating from the neural crest. It originates from any region of the central nervous system, but often emerges from the adrenal glands. In most cases, metastasis to lymph nodes, bone marrow, and bone affect survival rates adversely. Although neuroblastoma is considered as a completely familial disease at the beginning, familial cases constitute a small part of all cases. The major mutations identified in the pathogenesis of neuroblastoma include MYCN, ALK, PHOX2B, ATRX and TERT genes. Nevertheless, it is now known that not only genetic but also epigenetic aberrations of gene expression are involved in the pathogenesis of neuroblastoma as well as many other diseases. Epigenetic regulations which include histone modifications that regulate the chromatin structure; DNA methylation which is involved in the control of gene expression; and ncRNAs, is being searched in relation to neuroblastoma. Conventional treatment includes surgical removal of tumors, chemotherapy, autologous stem cell transplantation, radiotherapy approaches according to the prognostic features of the patients, however, res...

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“…Unlike many cancers, TP53 mutations occur less frequently in neuroblastoma. The inhibition of protein phosphatase, Mg 2+ /Mn 2+ dependent 1D (PPM1D/Wip1), which is a negative regulator of TP53 mediated cell-death pathway, has been proposed as a novel approach to induce apoptosis through neuroblastoma cells through checkpoint kinase 2 (CHK2)/TP53 [73]. The novel identified proapoptotic brain expressed X-linked (BEX) genes in the downstream of the TP53 signaling pathway are promising as new tumor suppressors by inducing apoptosis in neuroblastoma cells [74].…”

Section: Targeted Treatment Approach and Future Perspectivesmentioning

confidence: 99%

Molecular Approach to Neuroblastoma

Bağca¹,

Avcı²

2017

Neuroblastoma - Current State and Recent Updates

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Neuroblastoma is a notably malignant cancer originates from neuroblastoma stem cells during embryogenesis. It can originate from any region of the peripheral nervous system. Neuroblastoma is a heterogeneous cancer. The cells responsible for heterogeneous structure are neuroblastoma stem cells that initiate the cancer and generate into all the cancer cells and have self-renewal property. Although some specific surface markers and genetic patterns of neuroblastoma stem cell were determined, all mechanisms have not been illuminated yet. Mutations that are specific to neuroblastoma development, risk group, and disease-stage are identified. However, epigenetic dysregulations also play major roles in the development of neuroblastoma. Patients gradually develop resistance to conventional chemotherapy or relapse occurs after treatment. New therapy approaches have been developed, either as alternatives to conventional chemotherapy, or in combination with it, in order to overcome the handicaps. Targeted therapies, those directly affecting the cancer cell or the cancer stem cell and having a minimal effect on healthy cells, constitute these approaches. Since neuroblastoma is highly heterogeneous both genetically and epigenetically, the data obtained from molecular mechanisms will greatly contribute to the survival of patients.

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Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Cited by 31 publications

References 50 publications

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

Molecular Approach to Neuroblastoma

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