Anti-mitotic therapies in cancer

Tischer, Julia; Gergely, Fanni

doi:10.1083/jcb.201808077

Cited by 77 publications

(61 citation statements)

References 10 publications

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“…Since both topoisomerase inhibitors, such as doxorubicin or etoposide, and HDAC inhibitors are known to cause direct or indirect DNA damage, respectively, it is likely they might overcome resistance by potentiating the level of DNA damage in 177 Lu-RIT-targeted cells (24–26). Therefore, we focused on the third group of compounds, the mitotic kinase inhibitors, that affect kinases with critical functions for both mitotic entry and exit, and have a role in termination of the DNA damage-induced G 2 -checkpoint (27–29). In particular we further explored the combination of 177 Lu-lilotomab satetraxetan with the dual CDK1/2-Aurora A/B inhibitor JNJ-7706621, the Aurora A inhibitor alisertib (MLN8237), and the Plk1 inhibitor GSK461364, respectively.…”

Section: Resultsmentioning

confidence: 99%

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines

et al. 2019

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The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently being evaluated in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL). Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in two resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to RIT, alongside topoisomerase and histone deacetylases (HDAC) inhibitors.

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Section: Resultsmentioning

confidence: 99%

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines

et al. 2019

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“…Aurora kinases are known to play pleiotropic roles during mitosis. They are notably important for the capture, alignment, and segregation of chromosomes and thus were subjects of intensive screening campaign to characterize new potent inhibitors: 50+ clinical trials were performed in solid and hematological tumors [45]. Following the screening of kinases, we showed that P3 decreased the viability of two- and three-dimensional cell cultures and induced apoptosis of U-2 OS cells.…”

Section: Discussionmentioning

confidence: 99%

Kinase-Based Screening of Marine Natural Extracts Leads to the Identification of a Cytotoxic High Molecular Weight Metabolite from the Mediterranean Sponge Crambe tailliezi

et al. 2019

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Regulated cell death (RCD) results from the activation of one or more signal transduction modules both in physiological or pathological conditions. It is now established that RCD is involved in numerous human diseases, including cancer. As regulated cell death processes can be modulated by pharmacological tools, the research reported here aims to characterize new marine compounds acting as RCD modulators. Protein kinases (PKs) are key signaling actors in various RCDs notably through the control of either mitosis (e.g., the PKs Aurora A and B) or necroptosis (e.g., RIPK1 and RIPK3). From the primary screening of 27 various extracts of marine organisms collected in the Mediterranean Sea, an extract and subsequently a purified high molecular weight compound dubbed P3, were isolated from the marine sponge Crambe tailliezi and characterized as a selective inhibitor of PKs Aurora A and B. Furthermore, P3 was shown to induce apoptosis and to decrease proliferation and mitotic index of human osteosarcoma U-2 OS cells.

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“…The results of our study suggest that the canonical centrosomal pathway and the NuMA-mediated acentrosomal pathway complementally regulate bipolar spindle assembly in somatic cells, and that the latter becomes predominant in the absence of centrosomes (Figure 2). Understanding the multiple pathways that ensure robust bipolar spindle formation will assist in the design of anticancer drugs that target spindle assembly (Henriques et al, 2019;Tischer and Gergely, 2019).…”

Section: Chinen Et Al 2020mentioning

confidence: 99%

Centrosomal and Non-centrosomal Functions Emerged through Eliminating Centrosomes

Takeda

Kuroki

Chinen

et al. 2020

Cell Struct. Funct.

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Centrosomes are highly conserved organelles that act as the major microtubuleorganizing center (MTOC) in animal somatic cells. Through their MTOC activity, centrosomes play various roles throughout the cell cycle, such as supporting cell migration in interphase and spindle organization and positioning in mitosis. Various approaches for removing centrosomes from somatic cells have been developed and applied over the past few decades to understand the precise roles of centrosomes. Centrinone, a reversible and selective PLK4 (polo-like kinase 4) inhibitor, has recently emerged as an efficient approach to eliminate centrosomes. In this review, we describe the latest findings on centrosome function that have been revealed using various centrosome-eliminating approaches. In addition, we discuss our recent findings on the mechanism of centrosome-independent spindle bipolarization, discovered through the use of centrinone.

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Anti-mitotic therapies in cancer

Abstract: Tischer and Gergely review the cell biology behind microtubule poisons and their clinical use in cancer patients.

Cited by 77 publications

References 10 publications

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines

The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines

Kinase-Based Screening of Marine Natural Extracts Leads to the Identification of a Cytotoxic High Molecular Weight Metabolite from the Mediterranean Sponge Crambe tailliezi

Centrosomal and Non-centrosomal Functions Emerged through Eliminating Centrosomes

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