Mitotic Catastrophe

Souza, Raquel De; Ayub, Lais Costa; Yip, Kenneth W.

doi:10.1002/9781119432463.ch23

“…There is an ongoing debate on whether MC is a specific cell death program by itself or a previous event process leading to apoptosis or necrosis. 26,27 We observed that MC appeared earlier (ie, 24 h) than apoptosis; however, at a later time point (ie, 48 h), the proportion of cells involved in apoptotic cell death was extremely higher than the proportion of cells undergoing MC at an earlier time point (ie, 24 h). It is likely that the MMAE-induced apoptosis in our model may also be activated independently of MC in noncycling cells.…”

Section: Dovepressmentioning

confidence: 79%

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Falgàs

¹

,

Pallarès

²

,

Unzueta

³

et al. 2021

IJN

View full text Add to dashboard Cite

Background and Purpose Around 40–50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4 + ) and associated with poor prognosis. Methods The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4 + DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4 + DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs. Results We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4 + DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4 + DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs. Conclusion T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4 + DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4 + DLBCL patients.

show abstract

“…Unscheduled mitotic entry in the presence of DNA damage is rare, and it occurs primarily in response to chemo- or radiotherapy in cancer cells defective in checkpoint signaling. Under these conditions, cells undergo catastrophic mitoses producing abnormal nuclear morphologies due to defective chromosome segregation (comprehensively reviewed in reference [ 49 ]).…”

Section: Introductionmentioning

confidence: 99%

Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP

Rychłowska

¹

,

Agyapong

²

,

Weinfeld

³

et al. 2022

J Virol

View full text Add to dashboard Cite

show abstract

“…Unscheduled mitotic entry in the presence of DNA damage is rare, and it occurs primarily in response to chemo- or radiotherapy in cancer cells defective in checkpoint signaling. Under these conditions, cells undergo catastrophic mitoses producing abnormal nuclear morphologies due to defective chromosome segregation (comprehensively reviewed in (49)).…”

Section: Introductionmentioning

confidence: 99%

Zika virus induces mitotic catastrophe in human neural progenitors by triggering unscheduled mitotic entry in the presence of DNA damage while functionally depleting nuclear PNKP

Rychłowska

¹

,

Agyapong

²

,

Weinfeld

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Vertical transmission of Zika virus (ZIKV) leads with high frequency to congenital ZIKV syndrome (CZS), whose worse outcome is microcephaly. However, the mechanisms of congenital ZIKV neurodevelopmental pathologies, including direct cytotoxicity to neural progenitor cells (NPC), placental insufficiency, and immune responses, remain incompletely understood. At the cellular level, microcephaly typically results from death or insufficient proliferation of NPC or cortical neurons. NPCs replicate fast, requiring efficient DNA damage responses to ensure genome stability. Like congenital ZIKV infection, mutations in the polynucleotide 5’-kinase 3’-phosphatase (PNKP) gene, which encodes a critical DNA damage repair enzyme, results in recessive syndromes often characterized by congenital microcephaly with seizures (MCSZ). We thus tested whether there were any links between ZIKV and PNKP. Here we show that a PNKP phosphatase inhibitor inhibits ZIKV replication. PNKP relocalized from the nucleus to the cytoplasm in infected cells, co-localizing with the marker of ZIKV replication factories (RF) NS1 and resulting in functional nuclear PNKP depletion. Although infected NPC accumulated DNA damage, they failed to activate the DNA damage checkpoint kinases Chk1 and Chk2. ZIKV also induced activation of cytoplasmic CycA/CDK1 complexes, which trigger unscheduled mitotic entry. Inhibition of CDK1 activity inhibited ZIKV replication and the formation of RF, supporting a role of cytoplasmic CycA/CDK1 in RF morphogenesis. In brief, ZIKV infection induces mitotic catastrophe resulting from unscheduled mitotic entry in the presence of DNA damage. PNKP and CycA/CDK1 are thus host factors participating in ZIKV replication in NPC, and probably pathogenesis.

show abstract

Mitotic Catastrophe

Cited by 5 publications

References 145 publications

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP

Zika virus induces mitotic catastrophe in human neural progenitors by triggering unscheduled mitotic entry in the presence of DNA damage while functionally depleting nuclear PNKP

Contact Info

Product

Resources

About