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Mechanisms of Drug-Induced Mitotic Catastrophe in Cancer Cells

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Mechanisms of Drug-Induced Mitotic Catastrophe in Cancer Cells Current Pharmaceutical Design, 2010, 16, 69-78 69 Mechanisms of Drug-Induced Mitotic Catastrophe in Cancer Cells José Portugal*, Sylvia Mansilla and Marc Bataller Instituto de Biologia Molecular de Barcelona, CSIC, Parc Cientific de Barcelona. Baldiri Reixach, 10, E-08028 Barcelona, Spain Abstract: Mitotic catastrophe is a mechanism of cell death characterized by the occurrence of aberrant mitosis with the formation of large cells that contain multiple nuclei, which are morphologically distinguishable from apoptotic cells. Sometimes, mitotic catastrophe is used restrictively to indicate a type of cell death that occurs during or after a faulty mitosis leading to cell death, which takes place via necrosis or apoptosis, rather than a cell death itself. Several antitumor drugs and ionizing radiation are known to induce mitotic catastrophe, but precisely how the ensuring lethality is regulated or what signals are involved is barely characterized. The type of cell death resulting from antitumor therapy can be determined by the mechanism of action of the antitumor agent, dosing regimen of the therapy, and the genetic background in the cells being treated. Wild-type p53 promotes apoptosis or senescence, while mitotic catastrophe is independent of p53. Mitotic catastrophe can be regarded as a delayed response of p53-mutant tumors that are resistant to some damage. In this context, the elucidation of the mechanisms of treatment-induced mitotic catastrophe should contribute to an improvement of the antitumor therapy, because most of the solid tumors bear an inactive p53 protein. Keywords: Mitotic catastrophe, apoptosis, DNA-binding drugs, cell cycle, chemotherapy. INTRODUCTION occurs as a result of the uncoupling of the onset of mitosis after Cell death is usually considered to occur by p53-mediated DNA replication. Therefore, it has been considered an abnormal apoptosis [1, 2]. However, recent advances have led to the appre- mitosis leading to cell death, rather than a form of cell death [19]. ciation of additional, non-apoptotic, cell death pathways, which can DNA damage activates p53, and there are grounds for considering be either p53-dependent or p53-independent [1, 3-5]. DNA damage that wild-type p53 can promote apoptosis or senescence, while it is appears to induce several cell death pathways, only part of which not required for mitotic catastrophe [3]. Mitotic catastrophe is fall within the classical definition of apoptosis. In response to DNA fundamentally regarded as different from apoptosis [3, 20], yet damage wild-type p53 becomes stabilized promoting cells to several in vivo and in vitro models have shown that the different undergo either apoptosis or cell-cycle arrest [1-3, 6]. Cell cycle pathways of cell death are somewhat associated, and mitotic catas- arrest can be used to repair any damage, while apoptotic response is trophe is sometimes accompanied by the release of pro-apoptotic a genetically controlled response for cells to commit suicide when proteins and caspase activation, which would entail that mitotic repair cannot be accomplished [7]. The absence of wild-type p53 catastrophe shares some events used to define apoptosis [12, 21, function is the most common molecular abnormality in cancer cells 22]. and it is thought to play a key role in carcinogenesis [1, 5], and p53- It is noteworthy that cells need to evade the apoptotic pathway null mice are highly prone to developing cancer [1]. to become malignant, while a weakened mitotic checkpoint — Chemotherapy and radiation are known to inhibit tumor cell which is frequently observed in cancer cells—, together with the proliferation. So far, the best-studied antiproliferative response to absence of functional p53, may prompt cells to undergo mitotic chemotherapeutic agents is apoptosis, and thus a prevalent model to catastrophe after chemotherapy [4, 5, 18]. In general, the suscep- explain how cancer therapy can reach its goals has been that tibility of tumor cells to apoptosis (defined as “a caspase-mediated antitumor drugs trigger the cells to undergo apoptotic death, often cell death with associated apoptotic morphology” [23], which is mediated by wild-type p53 [1, 7], and that, therefore, cells resistant commonly accompanied by functional wild-type p53 activity [7]) is to apoptosis may become resistant to chemotherapy [1, 6, 7]. How- severely distorted. This renders other forms of cell death, such as ever, other mechanisms of cells death such as mitotic catastrophe mitotic catastrophe and necrosis, more important. Moreover, after may be also important to explain the success in anticancer therapy treatment with drugs or radiation, some cells containing functional [1, 3, 4, 8] (Table 1). p53 may undergo growth arrest with phenotypic features of cell senescence, reviewed in refs. [24-26]. MITOTIC CATASTROPHE IN TUMOR CELLS We should query about what determines the mode of cell death Here, we review the recent advances in the understanding of induced by a particular antitumor drug. The answer is rather com- some molecular pathways operative in non-apoptotic and apoptotic plex, and we have to consider several factors such as the cell type, cell death and of any cross-talk among them. To this end, we pay the genetic background of the cell, the type of DNA damage and the attention to phenotypic changes and molecular mechanisms dose of the drug used [5, 14, 24, 27, 28]. In general, tumors arising involved in the development of mitotic catastrophe. Mitotic from thymocytes, including T-cell lymphomas, spermatogonia, catastrophe is used to describe cell death that occurs during or after some hematological cancers, or bone marrow are often sensitive to a faulty mitosis, usually ending in polyploidy together with the the induction of apoptosis and display a clear overall response after formation of cells that contain multiple nuclei [9-14]. It has been treatment with DNA-damaging agents, which is generally p53- described as the principal form of cell death induced by ionizing dependent [1]. In contrast, for most solid tumors, which usually radiation [3, 9, 15, 16] and has been identified as the main response contain non-functional p53, the primary cell death pathway after to several antitumor drugs [3, 13, 14, 17, 18]. Mitotic catastrophe treatment with DNA-damaging agents may involve mitotic catastrophe [1, 4, 8]. *Address correspondence to this author at the Instituto de Biologia CELL CYCLE CHECKPOINTS AND THE RISE OF Molecular de Barcelona, CSIC, Parc Cientific de Barcelona. Baldiri MITOTIC CATASTROPHE Reixach, 10, E-08028 Barcelona, Spain; Tel: +34-93- 403 4959; Fax: +34- 93- 403 4979; E-mail: [email protected] Once DNA damage occurs, cells can stop progression through the cell cycle to allow for the damage to be repaired [29]. The phase 1381-6128/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. 70 Current Pharmaceutical Design, 2010, Vol. 16, No. 1 Portugal et al. Table 1. Summary of Several Pathways of Cell Death Observed in Drug-Treated Cellsa Apoptosis Mitotic catastrophe Necrosis Definition and * Programmed cell death. * Cell death occurring during or after a *Identifies, in a negative fashion, cell characteristics * Cells shrink with blebbing of cell faulty mitosis. death lacking the features of apoptosis membranes. * Giant cells with two or more nuclei or autophagy. * Condensed chromatin and DNA and partially condensed chromatin. * Cells visible swell with breakdown of fragmentation. * Can lead to necrosis or apoptosis-like cell membrane. death (p53-independent). * Typical nuclei with vacuolization, and disintegrated cell organelles. Associated genetic * Stimulated by cyclin D1 activation and * Stimulated by deficiencies in proteins * In general, it is not considered changes by Myc. involved in G1 and G2 checkpoints and genetically determined (this is open to * Can be inhibited by loss of wild-type in mitotic spindle assembly: p53, p21, debate). p53. Cdk1, Chk1, Chk2, etc. * Caspase activation. * Can follow caspase-dependent or – independent routes. Detection methods *Sub-G1 peak in flow cytometry. * Cells with two or more nuclei detected *Early permeability to vital dyes. *Annexin-V-staining. by Microscopy or Laser Scanning * Staining with propidium iodide. Cytometry. *Accumulation in G2/M and *Internucleosomal laddering, etc. *Electron microscopy. polyploidy. aOther antiproliferative responses, such as autophagy and induced senescence, have been reported [3, 4, 55, 61]. of the cell cycle in which the cells arrest depends, in part, on their chromosome replication has not been completed, problems linked p53 status. Cells with wild-type p53 halt predominantly in G1, to DNA strand breaks might commit cells to die because they bear while cells with defective p53 (which occurs in more than 50% of chromosome deficiencies. Appropriate sensors detect incomplete human tumors) fail to arrest in G1 but rather arrest in S or G2 phase DNA replication, and the signal is then transmitted to kinases such [30, 31]. as ATR, which phosphorylate and activate other kinases such as Chk1 [32] and Fig. (1). The initiation of mitosis is turned on by the Cyclin-dependent kinases (Cdks) play a central role in checkpoint activation [32]. In the G1 phase of the cell cycle, DNA timely activation of the cyclin B-cdc2 complex [37, 38]. The checkpoint Chk1 and Chk2 kinases are essential for cell-cycle arrest damage activates p53, which in turns activates the expression of p21WAF1, a Cdk inhibitor. The induction of p21WAF1 is the major before mitosis in response to DNA damage and DNA replication blockage respectively [37-39]. Chk1 is phosphorylated at Ser317/345 mechanism underlying G1 arrest caused by DNA damage. Enhanced p21WAF1 expression can also lead to cell growth arrest in in response to DNA damage, and it seems to play a role at every G2 after DNA damage, by inhibiting the activity of cyclin- point in the cell cycle [40, 41]. Chk1 is subjected to multiple regulations, including transcriptional suppression by p53. A study dependent kinases, with p53 playing a critical role in halting cells at the G2 checkpoint [30].
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