Preferential killing of p53-deficient cancer cells by reversine

Jèmaà, Mohamed; Galluzzi, Lorenzo; Kepp, Oliver; Boilève, Alice; Lissa, Delphine; Senovilla, Laura; Harper, Francis; Pierron, Gérard; Berardinelli, Francesco; Antoccia, Antonio; Castedo, Maria; Vitale, Ilio; Kroemer, Guido

doi:10.4161/cc.20621

Cited by 35 publications

(44 citation statements)

References 57 publications

(75 reference statements)

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“…In contrast, elevated doses caused abortive mitosis leading to mitotic catastrophy and apoptosis in p53-deficient cells. 49 In addition, some mutants reveal gain-of-function 50 and some mutants, such as codon 175 mutations, are involved in DNA binding, but induces conformational changes as well. 51 Finally, p53 may induce apoptosis in a non-transcriptional way through direct binding to components of the bcl-2 system, such as bax.…”

Section: Tp53mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Tp53mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…Cell fate profiles are illustrated as previously described. 46,57 In vivo studies. The housing and handling of animals was performed in strict compliance with the European and German Guidelines for Laboratory Animal Welfare.…”

Section: Methodsmentioning

confidence: 99%

“…56 For the assessment of cell cycle distribution, cells were collected, stained with 50 mg/ml PI and analyzed by cytofluorometry as previously described. 46,57 For EdU incorporation assays, cells were incubated with 10 mM EdU for 30 min at 37 1C, fixed, permeabilized and stained with the fluorescent dye azide (Click-iT reaction cocktail; Molecular Probes-Life Technologies) and PI, according to the manufacturer's instructions. For the simultaneous measurement of DNA content and cyclin B1 levels, fixed cells were costained with 10 mM 4 0 , 6-diamidino-2-phenylindole (Molecular Probes-Life Technologies) and mouse antiserum specific for cyclin B1 (mouse monoclonal IgG1 no.…”

Section: Methodsmentioning

confidence: 99%

“…610219; BD Biosciences, San Diego, CA, USA) as previously reported. 46,57 Cytofluorometric acquisitions were performed on a FACSCalibur cytofluorometer (BD Biosciences) equipped with a 70-mm nozzle or a Gallios cytofluorometer (Beckman Coulter, Miami, FL, USA). Data were statistically evaluated using the CellQuest (BD Biosciences) or Kaluza (Beckman Coulter) software.…”

Section: Methodsmentioning

confidence: 99%

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Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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,5,6,11,12,13 Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2- [(2-cyanophenyl) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

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“…Later, some reports showed that reversine had a role in regeneration (Anastasia et al 2006;Kim et al 2007;Saraiya et al 2010;Anastasia et al 2010;Jung and Williams 2011). Moreover, a recent report showed that reversine had anti-tumor capabilities such as for a myeloma cell line (McMillin et al 2010), and demonstrated that reversine could suppress the expression of cell cycle related proteins Aurora kinase A (Aur-A) and Aurora kinase B (Aur-B), and also could suppress enzymes involved in cell growth signaling, such as JAK2 and SRC (McMillin et al 2010;Hua et al 2012;Shan et al 2007;Jemaà et al 2012;Kuo et al 2012;Hsieh et al 2007). However, the definite molecular signaling pathway of the anti-tumor effects of reversine has not yet been understood.…”

Section: Introductionmentioning

confidence: 99%

Synergistic antitumor activity of reversine combined with aspirin in cervical carcinoma in vitro and in vivo

et al. 2013

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A recent report showed that reversine treatment could induce murine myoblasts dedifferentiation into multipotent progenitor cells and inhibit proliferation of some tumors, and other reports showed that apoptosis of lung adenocarcinoma cells could be induced by aspirin. The aim of the present study was to evaluate the synergistic antitumor effects of reversine and aspirin on cervical cancer. The inhibition rate of reversine and aspirin on cervical cancer cell lines' (HeLa and U14) was determined by MTT method, cell cycle of HeLa and U14 cells was analyzed by FACS, mitochondrial membrane potential of HeLa and U14 was detected using a JC-1 kit. HeLa and U14 colony formation was analyzed by soft agar colony formation assay. The expression of caspase-3, Bcl-2/Bax, cyclin D1 and p21 was detected by qRT-PCR and Western Blotting. Moreover, tumor weight and tumor volume was assessed using a murine model of cervical cancer with U14 cells subcutaneously (s.c.) administered into the neck, separately or combined with drug administration via the intraperitoneal (i.p.) route. The inhibition rate of cells in the combination group (10 lmol/L reversine, 10 mmol/ L aspirin) increased significantly in comparison to that when the drugs were used alone (P \ 0.05); moreover, this combination could synergistically inhibit the proliferation of five cervical cancer cell lines (HeLa, U14, Siha, Caski and C33A). In the therapeutic mouse model, tumor weight and tumor volume of cervical cancer bearing mice was more reduced when compared with the control agents (P \ 0.05) in tumor-bearing mice. The combination of reversine and aspirin exerts synergistic growth inhibition and apoptosis induction on cervical cancers cells.

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Preferential killing of p53-deficient cancer cells by reversine

Cited by 35 publications

References 57 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

Synergistic antitumor activity of reversine combined with aspirin in cervical carcinoma in vitro and in vivo

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