REVIEW Open Access

Role of senescence and mitotic catastrophe incancer therapyRicha Singh, Jasmine George, Yogeshwer Shukla*

Abstract

Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered incancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce celleradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towardsdeath during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug expo-sure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senes-cent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death thatresults from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Differentclasses of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature ofthe inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mentionthat they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the useof senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancercontrol.

IntroductionThe incidence of cancer worldwide is on a rise, making itonly second to coronary heart disease [1]. Unifying prop-erty of cancer includes six canonical characteristics: selfsufficiency in growth signals, insensitivity to growth inhibi-tory signals (anti-growth), evasion of programmed celldeath (apoptosis), unlimited proliferation of diseased cells,sustained angiogenesis, intrusion of adjacent cells and tis-sues and metastasis to distant niches in the body [2].Genetic instability associated with telomere attrition

or cell cycle checkpoint dysfunction is an early event intumorigenesis. Telomeres are guanine rich tandemnucleotide repeats flanking the ends of chromosomes inall eukaryotic cells responsible for maintaining geneticintegrity and implicated in aging (senescence) and can-cer [3]. Cell cycle checkpoints or mitotic kinases (MKs)are the rigorous quality control steps of mitosis [4] thatfunction in preserving the fidelity and integrity of DNAand allow mitosis to continue with accurately function-ing DNA, spindle assembly, centrosome and kinetochorethus preventing cell death via mitotic catastrophe (MC).

MC therefore, refers to the process when cells attemptto divide without proper repair of DNA damage due tofaulty cell cycle checkpoint functioning consequentlyresulting in formation of giant, multinucleated cells withcondensed chromosomes, distinguishing MC morpholo-gically from other modes of cell deaths.Abundant data amassed from several laboratories have

provided innumerable instances to show that it is betterto cure this dreadful disease at preventable stage byearly diagnosis and consequent therapeutic intervention.Strategies for cancer treatment has generated significantinterest in the recent past and therefore, the focus ofresearch endeavors on understanding the mechanism ofcell death pathways applicable in treatment of cancerwhich include not only apoptosis but necrosis, autop-hagy, MC and in context of cancer therapy, senescencehas always been there [5].This review will explore major highlights on the role

of senescence and MC triggered in various cancers bychemotherapeutic intrusion and opens avenues forexpanding research work by comparing the resultsobtained so far.

* Correspondence: yogeshwer_shukla@hotmail.comProteomics Laboratory, Indian Institute of Toxicology Research, (Council ofScientific & Industrial Research), PO Box 80, MG Marg, Lucknow-226001, India

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© 2010 Singh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

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Senescence: Terminal growth arrest in dividing cellsThe term senescence is derived from the Latin wordsenex, meaning “old age” or “advanced in age”. Senes-cence at the cellular level is a physiological program ofcellular growth arrest that is triggered by the shorteningof telomeres or by stress [6]. This permanent growtharrest is also considered a type of cell death in the con-text of cancer therapy by some researchers [7,8] andsome consider it similar to the programmed cell deathby ‘apoptosis’ [9]. Senescence can be broadly categorizedinto two classes: accelerated or stress induced prematuresenescence (SIPS) and replicative senescence (RS) andboth are believed to be essential anti-carcinogenic pro-grams in normal cells. Accelerated senescence occurs inresponse to the activation of Ras/Raf pathways [10] andby supra-physiological mitogenic signaling [11]. Thephenomenon of RS was first described in the context ofnormal human cells explanted in culture that failed todivide beyond a finite number of fifty divisions [12] andit is a well-known defining property of euploid mamma-lian cells [13]. Telomere dynamics has been shown to bea critical component of both aging and cancer [14]. Tel-omeres, the highly repetitive DNA (TTAGGG sequence)which camouflages chromosome ends [15] preventnucleolytic degradation, end-to-end fusion, irregularrecombination, and other events that are normally lethalto a cell [15]. With each cell division a part of telomeregets eroded [16,17] and the chromosome being passedto the progeny gets the clipped off telomere.Thus genetic integrity is gradually lost with telomeres

progressively shortening after each division as a result ofend-replication problems and hence, is a conspicuousfeature in almost all dividing cells which do not expressor maintain sufficient telomerase activity to maintainthe telomeres. Telomerase reverse transcriptase(hTERT), whose amount is lessened after birth, func-tions by replenishing telomere by adding TTAGGGsequence at the 3’end of DNA. Telomerase activity ismeasured by TRAP assay or RT-PCR. Less frequentlyother alternative mechanism of telomere maintenancenamely Alternative Lengthening of Telomeres (ALT) isopted [18]. Telomere dysfunction (short telomeres) hasbeen associated with the initiation and progression ofmouse and human intestinal neoplasia [19] and mayalso increase the risk of developing epithelial cancers bya process of breakage-fusion-bridge that leads to the for-mation of complex nonreciprocal translocations (a clas-sical cytogenetic feature of human carcinoma) [20].Blood relative telomere length was found to represent astrong independent prognostic indicator in patients withadvanced breast cancer [21]. Similarly mean telomerelength was statistically shorter in case patients with headand neck cancer as compared with control as measuredwith the southern blot and quantitative-fluorescent in

situ hybridization assay [22]. Telomerase and p53 playcritical roles in tumorigenesis and senescence. Senescentcells exhibit distinct morphology in culture. They areenlarged and flattened with increased granularity [23]exhibit SA-b-gal staining and a characteristic senescenceassociated heterochromatin foci (SAHF) formation [24]and comparatively less dense culture than a confluentyoung culture probably because they are more sensitiveto cell-cell contact inhibition [12,13]. Even though theycannot divide under mitogenic stimulation yet theyremain metabolically and synthetically active in in vitroconditions for several years [24] but can not resume cellgrowth after drug withdrawal. SA-b-gal, the most widelyused surrogate marker with considerable specificity tosenescent cells appears to reflect an increased lysosomalmass [23]. Another marker is clusterin/apolipopterin J,is a highly conserved ubiquitously expressed secretedglycoprotein has been implicated in many physiologicalprocesses, gets upregulated during stress induced pre-mature senescence, in vivo aging, RS, in several agelinked deformities, neuropathological disorders like Alz-hiemers disease and dementia and has a direct relation-ship with human longevity [25]. Cellular senescence is apotent anti-cancer mechanism controlled by tumor sup-pressor genes, particularly p53 and pRb.Role of p53Telomere-induced senescence has been proved to be aseffective as apoptosis in reducing cancer incidence andis mediated by the tumor suppressor gene, p53 [26].Mutations in the p53 gene frequently appear in humantumors conferring aggressive oncogenic properties suchas exacerbated malignant transformation and metastaticphenotype when over-expressed in p53-null cells. P53gets activated upon genotoxic and non genotoxic stres-ses like oxidative damage and activates p21 and ulti-mately culminates the cell to senescence. Mice with apoint mutation (p53(R172H)) in their endogenous p53loci act as a model for the human Li-Fraumeni syn-drome. Genetic alterations at chromosomes 3p, 6p, and1lq were frequently found early in tumor developmentand showed additional allelic losses at chromosomearms 6q, 17p and 18q. Genes for telomerase suppressionare presumably located on chromosomes 3, 4 and 6 [27].P53 over expression has been directly associated with

unfavorable clinico-pathologic factors such as advancedstage, histologic subtype, advanced patient age andnodal metastasis in endometrial carcinomas while bcl-2expression was related with younger age, favorable gradeand PR expression by tumor cells. Patient survival ishowever not related to the tested biomarkers [28]. Inhumans, TP53 codon 72 Arginine to Proline poly-morphism was found to affect both cancer incidenceand longevity as well [29]. The senescence-associatedsignature of p53 isoform expression (that is, elevated

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p53beta and reduced Delta133p53) was observed in vivoin colon adenomas with senescent phenotypes. Theincreased Delta133p53 and decreased p53beta isoformexpression found in colon carcinoma may signal anescape from the senescence barrier during the progres-sion from adenoma to carcinoma [30].Other tumor suppressor genesP107 is required for the initiation of accelerated cellularsenescence in the absence of Rb and p130 may berequired to prevent the onset of this phenomenon in un-stimulated prostate cancer cells lacking a functional Rballele [31]. Cell cycle regulatory proteins are more sensi-tive to exogenous hormone treatment in postm-HBT(postmenopausal human breast tissue) than in pre-HBT(premenopausal human breast tissue) [32]. Olsson et aladvocates that bfl-1 (tumor suppressor bcl-2 familymember) contributes to chemo resistance and might be atherapeutic target in B-cell chronic lymphocytic leukae-mia [33]. The activation of PI3K/Akt pathway is involvedin the late-stage progression and metastasis of gastriccancer and attenuation of p-Akt by 2-ME suppressesmetastasis [34]. Yet another tumor suppressor Promyelo-lytic leukemia (PML) regulates p53 acetylation in bothRS as well as Ras induced accelerated senescence [35].Senescence in cancer cells: In vitro studiesA large number of in vitro studies have been reportedwhere a wide range of chemotherapeutical antidotesinduce senescence like morphological changes and SA-b-gal expression in cancer cells activating the pathwayof senescence. Research into the induction of cellularsenescence as cancer therapy has however, been hin-dered by a lack of compounds that efficiently inducethis response. To overcome this, Ewald et al (2009) byusing dual Hoechst 33342 and SA-b gal staining identi-fied library compounds that induce senescence in pros-tate cancer cells [36]. It is well acknowledged thattelomerase and the maintenance of telomeres are keyplayers in the ability of stem and cancer cells to bypasssenescence and be immortal. Proliferation of telomerase(-) pre-malignant cells leads to telomere dysfunctionand increased genomic instability suggesting one possi-ble sequence of events leading to immortalization ofbreast epithelial cells during cancer progression [37].The increased h-TERT expression may be a cellularresponse to genomic insults by various metal toxicantslike arsenic that may also act as a tumor promoter inmammalian carcinogenesis as studied in blood cells byMumford et al hTERT-specific T cells could contributeto the immunosurveillance of breast cancer suggestsnovel opportunities for both therapeutic and prophylac-tic vaccine strategies for cancer [38].In one of the studies, using non-small lung adenocar-

cinoma A549 cells, it was shown that after treatmentwith DNA damaging anti-tumor drugs like caffeine, cells

become permanently growth-arrested as a result of so-called drug-induced premature senescence (pseudo-senescence) or SIPS. Similarly, lowered efficacy of anti-cancer doxorubicin (due to dose dependent toxicity)against breast cancer cells can be increased when usedin conjunction with siRNA inhibitor of telomerase [39].Yet another study advocated the use of GRN163L (noveltelomerase template antagonist) in the treatment ofbreast cancer by augmenting the effects of paclitaxel[40]. Hence clearly proposing that inhibition of telomer-ase is a potential treatment strategy for inducing senes-cence. It has also been shown that caveolin-1 targetsMdm2/p53-mediated pathway and causes senescence inbreast cancer cells [41]. Another study reported thatbleomycin, a widely used anti-tumor agent, causessenescence of lung cancer cells by modulating the rolesof caveolin-1, a protein abundant in lung fibroblasts andsmooth muscle and endothelial cells [42].A recent study showed that the activation of the p53-

p21(Cip1/WAF1) pathway acts as a major mediator of cel-lular senescence induced by CKII inhibition in HCT116colon carcinoma cells [43]. A senescence-inducing effectof doxorubicin on the same cells, in another study, had adual effect-it stopped the proliferation of the majority ofthe cells and led to the appearance of proliferating aneu-ploid cells [44]. Likewise, while characterizing ashwa-gandha and its molecular mechanisms Wadhwa et alprovided the first example that phytochemical(s) haveboth anti-cancer and anti senescent activities and pointedtowards the molecular link between aging and cancerusing normal human fibroblasts through decreased accu-mulation of molecular damage, down-regulation of theSA-b gal activity and the senescence marker protein, p21(WAF-1), protection against oxidative damage, and induc-tion of proteasomal activity [45]. In one of the studies, bysilencing BRCA1 expression at different levels throughRNA interference technology in a series of partially trans-formed (HBL100) and tumorigenic (MCF7 and T47D)breast cancer cell lines, cell models were probed by clono-genic assay for their response to several DNA-damagingagents (mitomycin C, cisplatin, doxorubicin, and etopo-side) commonly used in cancer therapy [46]. Theincreased sensitivity to these compounds displayed byBRCA1-defective cells was correlated to an increased frac-tion of growth-arrested, enlarged, multinucleated SA-b-galactosidase-positive senescent cells [46]. Melanocyticnevi frequently harbor oncogenic BRAF mutations andrecently it was found that a subpopulation of melanocytespossess the ability to survive BRAF induced senescence,and suggest that p53 inactivation may promote malignanttransformation of these cells [47] and thus have implica-tions in skin cancer treatment. In vitro experiments withtherapeutic nucleic acids successfully inhibited E6/E7oncogene expression and caused induction of apoptosis

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and/or senescence in cervical carcinoma cells. A usefulassay was described by Lau et al [48] to predict theresponse of the patient to a set of medicines withoutadministering them by testing the susceptibility of a sam-ple of cancer cells in vitro and comparing it to the stan-dard regimen.Apart from these, it has been observed that cells’ pas-

sage number controls the appearance of senescence.Normal human diploid fibroblasts approach senescencenear passage 64 through RNaseT2 expression, whichhowever fails to induce senescence in SV40 immorta-lized cell lines [49]. Rat chondrocytes show the onset ofsenescence in the 4th passage [50] while human rheuma-toid arthritis fibroblast-like synoviocytes exhibit ageingat 10th passage [51]. Stable clones derived from hTERT-expressing normal and G6PD-deficient fibroblasts havenormal karyotypes, and display no sign of senescencebeyond 145 and 105 passages, respectively, suggestingthat ectopic expression of hTERT, in addition to telo-mere length maintenance by activating telomerase, alsofunctions in regulating senescence induction [52].Recently, a study explored the self-renewal potential ofhuman breast stem cells and found that it getsexhausted within five in vitro passages of mammo-spheres, suggesting the need for further improvisation inculture conditions for their long-term maintenance [53].Senescence in animal models: In vivo studiesInduction of senescence upon drug administration hasbeen proposed as a possible anti-cancer treatment invarious animal models. The finite proliferative potentialof normal human cells leads to RS, which is a criticalbarrier to tumor progression in vivo. By studyingembryonic fibroblast-derived cells with loss-of-senes-cence or H-RasV12/E1A-transformed phenotypes at dif-ferent stages of oncogenic progression in nude mice, itwas postulated that they may escape therapies aimed atmetabolic inhibition of tumors with a fully developedWarburg phenotype [54]. b-carotene provides protectionagainst O3-induced skin oxidative stress in female SKH-1 mice skin, which is consistent with a protective rolefor beta-carotene in the skin hence has implications inskin cancer and aging or senescence of skin [55]. Anovel target of NESH-SH3 (TARSH), cellular senescencerelated gene in mouse embryonic fibroblasts may sup-press tumor development in pulmonary tumorigenesismouse model by causing an increase in SA-b-gal activityand this was attributed to p53-dependent p21(Cip1) accu-mulation [56]. Pituitary tumor transforming gene dele-tion results in pituitary p21 induction and abrogatestumor development in Rb(+/-)Pttg(-/-) mice. Senescencewas evidenced by increased p21 and SA-b-galactosidase.Aneuploid pituitary cell p21 may constrain pituitarytumor growth, thus accounting for the very low inci-dence of pituitary carcinomas [57]. Work by Efimova et

al using p38-null mice skin carcinogenesis modelstrongly suggests a role for p38delta (key regulator insenescence, tumorigenesis, survival, inflammation etc) inpromoting cell proliferation and tumor development inepidermis and may have therapeutic implication for skincancer [58]. Three xenograft breast cancer mouse mod-els, 2 of them with a TP53 mutation and one without it,were studied for their immediate response to high dosesof epirubicin-cyclophosphamide. TP53 wild type stainedpositive for SA-b-galactosidase staining and also overexpressed P21 but TP53 mutant did not succumb tosenescence suggesting that treatment induced senes-cence is mediated via functional p53 in breast cancer[59]. More in vivo studies are however, needed to eluci-date the role of senescence in cancer. Although theseconcepts are well supported in these models, translatingthem to clinical oncology remains a challenge.Neosis - Achilles heel of cancer cells evading senescenceThe physiological phenomenon of senescence serves as alucrative pathway to annihilate deleterious cancer cellsand tissues. This program of senescence is activated uponthe administration of various anti-cancer regimens. Eventhough this is not a universal mechanism of curbingtumor cell growth, yet a considerable number of instancesof in vitro as well as in vivo studies have been cited todecipher the metabolic pathway it targets and these stu-dies have produced useful results that have enhanced andrefined our knowledge about these pathways (Figure 1)and will be helpful in delineating new treatment strategiesfor curtailing cancer. Several studies [60,61], however pro-vide compelling evidence that some cancer cells which aremitotically non-viable escape cell death, due to the accu-mulation of some genetic and epigenetic mutations andp53/pRB/p53Ink4a-dependent senescence checkpoint mal-functioning resulting in telomerase dysfunction [61,62]and finally evade cell death via continued progressionthrough neosis. Such cells acquire so called’ immortality’and to eliminate them, different strategies need to bedesigned. These cells multiply by a unique route called‘neosis’ that facilitates in its progression and existencethereby evading the program of senescence. It has beendescribed as a parasexual, somatic, reduction division incancer [62]. Although neosis-like events have beenreported in the literature sporadically for more than a cen-tury [63] under different names, they have been neglecteddue to the lack of appreciation of the significance of thisprocess in cancer biology. Neosis may be a fundamentalstep in current concept of multi step carcinogenesis.Studying the behavior of individual neotic clones hasrevealed the significance of their central role in cancer[64]. Non-synchronous occurrence of secondary/tertiary-neosis (Figure 2) creates the illusion of the existence ofcancer stem cells and the ‘mirage’ of immortality of cancercells.

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Figure 1 Genes involved in senescence.

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Some of the genetic and epigenetic alterations becomethe achilles heel of the mutated tumors that bypass theeffect of certain classes of anti-cancer agents. That is,patients whose tumors carry such defects can be strati-fied for respective therapy rendering some classic DNAdamaging agents called neosicides into “targeted thera-pies.” Development of novel strategies to improve cur-rent status of cancer therapy will require identificationand exploitation of yet unrecognized differences betweennormal and tumor cells with respect to propagation,evolution and development of resistance to conventionaltreatments [65]. The discovery of neosis has identifiednovel cellular targets, against which one can identifynovel neosis-specific molecular targets in order to

design anti-neotic agents or neosicides that will be morespecific in their action and do less harm to non diseasedcells. A judicial combination of senescent drugs withefficient neosicides could further improve the status ofcancer control.MC and role of MKs in cancerAccording to the tenets of cancer biology, tumor cellsarise after about 13 mitotic divisions of the initiated cell[66]. MKs, are rigorous quality control steps of mitosisand function in preserving the fidelity and integrity ofDNA and allow mitosis to continue only with accuratelyfunctioning DNA, spindle assembly, centrosome andkinetochore thus preventing MC [67]. Malfunctioning ofMKs are intimately involved in the development of

Figure 2 Prerequisites for the onset of neosis and step-wise depiction of primary neosis (P/neosis) and secondary and tertiary neosis(S/T neosis). When a normal diploid cell accumulates genetic mutation owing to exposure, either dies following apoptosis or necrosis or mayenter mitotic crisis and after repair again re-enters cell cycle or may become tetraploid after few hours or become polyploidy and succumb tosenescence or may circumvent senescence and divide by neosis. Neosis of non-viable NMCs may give rise to genetically viable daughter cells‘Raju cells’ by P/neosis and further divide and re-divide by S/T neosis. The number of progenies may vary from one to infinite and differ fromNMCs and other daughter cells unlike conventional mode of division, mitosis. Number of surviving progenies depends on the ‘survival of thefittest’.

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errors in a vast majority of solid tumors and hematolo-gical malignancies. MC is an event in which a cell isdestroyed during mitosis. This is believed to be causedthrough apoptosis as a result of an attempt at aberrantchromosome segregation early in mitosis, or as a resultof DNA damage later, during the metaphase/anaphasetransition. Cells which fail to go through a MC aftermitotic failures are likely to create aneuploid cells whenthey later reproduce, posing a risk of oncogenesis,potentially leading to cancer [67]. Hence MC is also inthe league of processes which participate in preventionof cancer. MC which has been described as ‘Deaththrough a tragedy’ [68] is stimulated by ionizing radia-tions (IR), chemotherapeutic drugs or hyperthermia andis caused by malfunctioning of cell cycle checkpointsand MKs. The normal choreography of the events in themitotic cell cycle gets disturbed and aneuploidy follows.An aneuploid cell can be hyperaneuploid and may con-tribute to tumorigenesis by an enhanced expression ofoncogenes or may be hypo-aneuploid and be liable fortumorigenesis by a loss of heterozygosity of varioustumor suppressor genes [69].MC shares several biochemical hallmarks of apoptosis,

in particular mitochondrial membrane permeabilizationand caspase activation [70] but is proposed to be funda-mentally different from apoptosis [71]. Both senescenceand MC are important pathways that cause cell annihi-lation upon chemotherapeutic intervention. Themechanism and morphology of the deceased cells ishowever different in both the cases. A tabular represen-tation of the differences between MC and senescence isgiven in Table 1.Genetic checkpoint defects lead to syndromes that

demonstrate chromosomal instability, increased sensitiv-ity to genotoxic stress and consequently cancer predis-position. The detection of persistent MK over-expression, particularly the Aurora kinase family, andcentrosome amplification in precursor/pre-malignantstages, strongly correlate these molecular changes inprecipitating the aneuploidy seen in many human neo-plasms [72]. The sustained over-expression and activity

of various members of the MK families, including Aur-ora kinases (A, B, C), Polo-like (Plk1-4), and Nek(NIMA1-11) in diverse human tumors strongly indicatethat these entities are closely involved in the develop-ment of errors in centrosome duplication, chromosomesegregation, and cytokinesis.MKs familiesThe focus of this section is on the different MKsfamilies. These kinases are modulated by de-novo synth-esis, stability factors, phosphorylation, and ubiquitin-dependent proteolysis. They, in turn, phosphorylateinnumerable centrosomal/mitotic protein substrates, andhave the ability to behave as oncogenes (i.e. Aurora-A,Plk-1), providing a compelling link between errors inmitosis and oncogenic processes [73]. Additionally, dys-regulation of MKs have been linked with improper cellcycle progression both in vitro and in vivo. Without get-ting into the basics of MKs, the main pre-clinical andclinical studies concerning MK inhibitors currentlyunder investigation are reported and important consid-erations for their future development are discussed.Here is given a representation of kinases in differentphases of cell cycle (Additional File 1: Table S1).Cyclin dependent kinases 1 (Cdk1)Cdk1 is vital participant in the mitotic cell cycle. Mitosisbegins and ends with the activity of cdk1 with bindingpartner cyclin B1. First studied in fission yeast (Sacchar-omyces cerevesiae), Nurse [74] identified a gene thatcontrolled mitosis and named it cdk1 or cdc2. Studieshave revealed that functional p53 protein may enhancethe anti-cancer activity of roscovitine (known cdk1 inhi-bitor) that could be beneficial for anti-cancer therapy[75]. Tumorigenecity mediated by p53 loss does notrequire either Cdk2 or Cdk4, which necessitates consid-eration of the use of broad spectrum cell cycle inhibitorsas a means of effective anti-Cdk cancer therapy [76].Gartner et al have reported for the first time reportedan association of cyclins and Cdks with the microtubulenetwork by immunoelectron microscopy and immuno-biochemical methods. Cyclins D, E, A and B as well asCdks 1, 2 and 4 were also found to be associated and

Table 1 Comparison between senescence and mitotic catastrophe

Characteristics Mitotic catastrophe Senescence

Definition Synonymous with ‘Terminal proliferation arrest’ may proceed withapoptosis or necrosis depending on molecular profile of the cell

Synonymous with ‘Terminal growth arrest’ Celldeath in context of cancer

Biomarker Multinucleated giant cells, no specific in vitro and in vivo assay available SA-b galactosidase expression, detected by X-gal staining

Morphology Aneuploidy, disrupted DNA index, micronuclei formation, nuclear envelopelacking, nuclear fragmentation and uncondensed chromatin

Flattened enlarged cells, granular cytoplasm,exhibit SAHF formation

Genotype implicatedin carcinogenesis

Accelerated by G1, G2 and prophase checkpoint proteins (ATM, ATR, p53,Chk2, Cdc25A, Cdc25B, Plk1 & 3)

Accelerated by telomere attrition, rasmutations, inhibited by ALT or p53

Inducing agents Hyperthermia, IR, anti-cancer drugs interfering with DNA or microtubuleassembly

Spontaneous as a result of cumulative divisionsor challenged by oncogenic stimulus

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exhibit kinase activity towards the microtubule-asso-ciated protein tau [77]. Bailet et al [78] have highlighteda new role for spleen tyrosine kinase (Syk) in regulatingcellular senescence and identify Syk-mediated senes-cence as a novel tumor suppressor pathway, the inacti-vation of which may contribute to melanomatumorigenicity. Study by Buchanan et al [79] on murineadenocarcinoma mammary cells provided new cluesregarding the mechanism involved in the modulation ofmammary tumor cell growth and survival induced byglypican-3. Gene expression profiling has generatedhypotheses that led to an increase in our knowledge ofthe cellular effects of seliciclib (cdk inhibitor) and couldprovide potential pharmacodynamic or response biomar-kers for use in animal models and clinical trials [80].Another Cdk inhibitor SU9516 is over expressed inHCT116 cells by the knockout of the p21WAF1/CIP1 genewhich suppresses thymidylate synthase and enhanceschemosensitivity to 5-Flurouracil [81].Check point kinases 1 (Chk1) and 2 (Chk2)Chk1 and Chk2 are effector kinases in the cellular DNAdamage response and impairment of their function isclosely related to tumorigenesis. If DNA damage isdetected after S and before G2/M transition, ATM/ATRis activated and phosphorylation of Chk1 and Chk2occurs [82] leading to cell death during mitosis or MC.Experiments have demonstrated that there are alternatemechanisms for activating ATM that are both stress-specific and independent of the presence of DNA breaks[83]. The activation of the ATR-Chk1 pathway inresponse to bifunctional DNA alkylator 1,3-bis(2-chlor-oethyl)-1-nitrosourea (BCNU) treatment and the depen-dency of this response on the DNA mismatch repaircapacity were investigated. Chk1 was found to be phos-phorylated at serine 345 and exhibited increased kinaseactivity. Si-RNA knockdown of ATR also reduced Chk1phosphorylation following exposure to BCNU. However,knockdown of ATM had no effect on the observedChk1 phosphorylation, suggesting that ATR was primar-ily responsible for Chk1 activation [84].Polo like kinases (Plk)A family of serine/threonine kinases also designated astubulin-associated proteins actively participate duringmitosis and comprises four distinct members: Plk1(Plk), Plk2 (Snk), Plk3 (Prk or Fnk) and Plk4 (Sak) [85]each carrying out a multitude of distinct roles. Plk1 isthe most extensively characterized among the familymembers, suggesting that the polo box domain of itcan provide an additional structural basis for discoveryof new anti-cancer drugs. It was also found out thatPlk1 is required for chromosomal DNA replicationunder stressful conditions [86] and Plk3 is more potentin inhibiting cell proliferation and inducing apoptosis[87].

Plk1 gene expression is tightly regulated with mRNAincrease beginning in S phase and peak mRNA levelsdetected at G2-M transitions and through mitosis [88].RNA-interference -mediated depletion of Plk1 to deter-mine its potential for sensitizing pancreatic tumor cellsto gemcitabine showed that small interfering RNA-mediated knockdown of Plk1 caused cell cycle arrest atG2/M and the reduction of cellular proliferation anddecreased cell viability and increased cellular apoptosis[89]. Transcription of Plk1 is inhibited along with otherG2/M specific genes like cyclin B1, cyclin B2 andcdc25B by inhibition of Nuclear Factor kappa B at G2-M phases [90]. Studies define and illuminate a late mito-tic function of Plk1 that it is obligatory in the position-ing and recruitment of Rho guanine nucleotideexchange factor (RhoGEF) Ect2 to the central spindleand abolishing RhoA GTPase localization to the equa-torial cortex, and suppressing cleavage furrow formationand cell division [91]. Increased plk-1 gene and proteinperhaps play a key role in abnormal proliferation ofacute leukemia cells and correlate with the malignancyof leukemia [92] prostate carcinoma, [93] and gastriccarcinoma [94]. Snk/Plk2 is transcriptionally down-regu-lated in B-cell neoplasms [95] and consequently pro-vides a potential mechanistic basis underlying the strongselective pressure for abrogation of Plk2 function in B-cell neoplasia. Plk3 has been shown to catalyse thepriming of Cdc25A by phosphorylated glycogen synthasekinase-3b (GSK-3b) and observations indicate that GSK-3b inactivation may account for Cdc25A overproductionin a subset of human tumors [96]. LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibi-tor of Plks and markedly enhances the anti-cancer activ-ity of paclitaxel [97] with anti-proliferative activityagainst human breast cancer [98].Aurora kinasesAurora kinases namely, Aurora A(Aurora 2), Aurora B(Aurora 1) and Aurora C(Aurora 3) are serine/threoninekinases also known as tubulin-associated proteins [99]which are expressed only in actively dividing cells andtheir increase is a factor of bad prognosis in cancer.Side effects, dosing and tolerability of inhibitors havebeen discussed in great length by Pinel et al [100] andenzymatic characterization of GSK1070916, a potentand selective Aurora-B/Aurora-C inhibitor was doneand compared with other Aurora inhibitors AZD1152and VX-680 [101], GSK1070916 was found to exert amore prevailing inhibitory effect due to a slow rate ofdissociation from the Aurora-B & C enzymes. Detailedkinetic analyses of two isogenic cell lines differing inp53 function and have been compared with the effectsof ZM447439 and VE-465 to describe several mechan-isms explaining how cells may evade killing by Aurora

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kinase inhibitors [102]. It has been proposed that periki-netochoric rings of MCAK and Aurora-B define a noveltransient centromere domain at least in mouse chromo-somes during meiosis and also its functions have beenillustrated by Parra et al [103].Bub related kinases (Bub family)The Bub family of kinases constitutes members that areconcerned with spindle assembly functioning and APC/C regulation. In one of the studies p53 was sustained toexpress in K562 leukemic cells after being infected byrecombinant adenoviruses carrying the wt-p53 gene andit was shown that wt-p53 can suppress excessive replica-tion of centrosomes and may contribute to the upregu-lation of Gadd45a and BubR1 protein expression as wellas the downregulation of Aurora A protein expression[104]. A novel study reports that Ajuba, a microtubule-associated protein collaborates with Aurora B andBubR1 at the metaphase-anaphase transition andensures proper chromosome segregation[105].Never in mitosis A- Related kinase (NIMA, Nek, Nrk)The Nek or Nrk related kinase family are essential MKsfirst described in the filamentous fungus Aspergillusnidulans [106] containing 11 members (Nek1, 2, 3, 6, 7,8, 9, and 11 are prominent) [107]. Nek1 is involvedearly in the DNA damage sensing/repair pathway afterIR and G(1)-S-phase checkpoint control can be rescuedby ectopically over-expressing wild-type Nek1. More-over, in cells without functional Nek1, DNA is notrepaired properly, double-stranded DNA breaks persistlong after low dose IR, and excessive numbers of chro-mosome breaks are observed [108]. Recently, studieshave explicated that ciliary localization of Nek8 in asubset of ureteric-bud-derived kidney tubules is essentialfor maintaining the integrity of those tubules in themammalian kidney [109].MKs and their role in cancer control- In a nutshellAs current cancer therapies are still in their infancy andare not able to fulfill the expectations of cancer control,strategies targeting mitotic regulators could be a poten-tially pragmatic option, which may improve the thera-peutic index when used either alone or in combinationwith current anti-cancer antidotes. The uniqueness ofMKs lies in the fact that they are expressed in activelyduplicating cells and not in differentiated cells furthermake it important targets against cancer cells. TargetingMKs would aid us in understanding the mechanism ofchemo-resistance. The research efforts to examine therole of MKs and mitotic signaling pathways are, how-ever, in its beginning. By presenting an overview of reg-ulation of MKs in this review, we open promisingavenues in designing novel therapeutic approaches incurbing cancer. Simultaneously, we also present therationale for these kinases as an anti-cancer target.Hence, more concern needs to be laid on in vivo work

to understand the role of MKs and their utility as tar-gets before we can actually embark on translational stu-dies in human.

Conclusions and future connotationsCancer is a global health problem and various treatmentstrategies are premeditated for curbing this deadly bio-medical manifestation. Cells continuously encounterDNA damage caused either by damaging agents, includ-ing oxygen radicals and DNA replication errors causedby stalled replication forks, or by extracellular environ-ments such as ultraviolet or IR. The cellular response toradiation or chemicals is complex and may lead to dif-ferent biological outcomes. Senescence, MC, necrosis,apoptosis and autophagy are such mechanisms out ofwhich the two former mechanisms have been discussedin this review.The physiological phenomenon of senescence is sti-

mulated by ras/raf activity, telomere attrition and p53.Cellular senescence is a persistently growth-arrestedphenotype in normal and transformed cells which maybe beneficial when used to target the proliferation oftumor cells or during organogenesis or wound healing.It is well known that cancer risk rises exponentially withage fuelled by somatic mutations. Senescence leads toaltered expression of genes (cell division control, cellstructure and metabolism) and imparts resistance tocells towards apoptosis apart from actively secretinginflammatory cytokines, proteinases and growth factors.Keeping all these aspects about this mechanism inmind, we can design novel treatment tactics in curbingcancer. The discovery of neosis has identified novel cel-lular targets, against which one can identify novel neo-sis-specific molecular targets in order to design anti-neotic agents or neosicides that will be effective againstmany tumor types and theoretically be expected to havea prophylactic action against multiple primary cancergrowths.Discussing the regulation of MKs, we open promising

avenues in designing novel biomarkers for novel unex-plored targets and present the rationale for these kinasesas an anti-cancer target. More in vivo work needs to beundertaken to understand the role of MKs and theirprospective as cellular targets before translational stu-dies can be performed in humans. Several key worksusing clinical samples strongly suggest that point muta-tions of the checkpoint genes contribute to malignanttransformation and genetic instability in cancer cells.However, the exact role of DNA damage checkpoints inthe prevention of human carcinogenesis should be re-evaluated. The spindle checkpoint inhibits the ubiquitinligase activity of the anaphase-promoting complex orcyclosome (APC/C), which is essential for mitotic pro-gression, until spindles are properly attached to all

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kinetochores, and thus prevents precocious chromosomesegregation. Because in a large proportion of tumors,cell cycle checkpoints are compromised and apoptoticpathways frequently suppressed, tumor cells preferen-tially execute this mitotic mode of cell death after treat-ment with DNA damaging regimens. A judicialcombination of anti-neosicides and anti-mitotic agentmay increase the therapeutic ratio under clinical set-tings. Moreover, results of recent important researchwork on senescence and MC can lay foundation ofother experiments targeting different cancers for testingefficacy of already tested drugs and on some cancers fordifferent drugs sharing similarities in chemical and phy-sical properties with known drugs.

Conflict of interestsThe authors declare that they have no competinginterests.

Additional file 1: Table S1. Roles of various kinases and substratesduring different cell cycle phasesClick here for file[ http://www.biomedcentral.com/content/supplementary/1747-1028-5-4-S1.DOCX ]

Authors’ contributionsRS composed the original manuscript. JG made extensive revisions andparticipated in manuscript preparation. YS edited and finalized the finalmanuscript. All authors read and approved the final manuscript.

Received: 5 January 2010Accepted: 21 January 2010 Published: 21 January 2010

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doi:10.1186/1747-1028-5-4Cite this article as: Singh et al.: Role of senescence and mitoticcatastrophe in cancer therapy. Cell Division 2010 5:4.

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