Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow and eventually spread through the body (metastasize) through continuous mitotic division. Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. What role does cancer drugs play in interrupting mitosis of cancer cells?
What is the role of mitosis in cancer?
Targeting Mitosis in Cancer: Emerging Strategies. The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades.
Why do mitosis-selective approaches to cancer treatment fail?
Granted the two main reasons behind failed mitosis-selective approaches are the underestimated slowness of human tumor-doubling time and the occurrence of mitotic slippage, one can envisage two possible ways to circumvent the complications: (i) antagonizing cancer-specific target that has oncogenic roles outside mitosis.
Can We target mitotic exit from cancer cells?
Pertaining to the high rates of mitotic slippages in cancer cells as a result of SAC-related mutations and the prevalent basal level of Cyclin B degradation, targeting mitotic exit has shown remarkable results thus far.
What is the role of mitotic cell death in chemotherapy?
The fragility of cancer cells when they undergo division serves as a critical intervention point in chemotherapy. This strategy encompasses a prolonged arrest of cells in mitosis, culminating in mitotic cell death (MCD).
How does mitosis affect cancer?
Mitosis occurs infinitely. The cells never die in cancer, as cancer cells can utilize telomerase to add many telomeric sections to the ends of DNA during DNA replication, allowing the cells to live much longer than other somatic cells. [3] With this mechanism, cancer cells that usually die simply continue to divide.
How does cancer treatment affect mitosis?
Chemo works by halting cancer cell division, often by interfering with RNA or DNA synthesis, and shrinking the tumor. The cell cycle goes from a resting phase, to an active phase, then to cell division (called mitosis).
Does mitosis prevent cancer cells?
Tumour-specific therapies. The clinical success of the microtubule toxins suggests that mitotic disruption is an effective anti-cancer strategy.
Why is the cell cycle important for prevention of cancer?
Cells have many different mechanisms to restrict cell division, repair DNA damage, and prevent the development of cancer. Because of this, it's thought that cancer develops in a multi-step process, in which multiple mechanisms must fail before a critical mass is reached and cells become cancerous.
What does mitosis mean in cancer?
A measure of how fast cancer cells are dividing and growing. To find the mitotic rate, the number of cells dividing in a certain amount of cancer tissue is counted. Mitotic rate is used to help find the stage of melanoma (a type of skin cancer) and other types of cancer.
What stage of mitosis does cancer occur?
1:5110:11Cell Cycle and Cancer: Phases, Hallmarks, and DevelopmentYouTubeStart of suggested clipEnd of suggested clipThe G in the g1.MoreThe G in the g1.
What is the purpose of mitosis?
The aim of mitosis is to separate the genome and ensure that the two daughter cells inherit an equal and identical complement of chromosomes (Yanagida 2014).
What is mitosis important?
Mitosis is important to multicellular organisms because it provides new cells for growth and for replacement of worn-out cells, such as skin cells. Many single-celled organisms rely on mitosis as their primary means of asexual reproduction.
Why Great mitotic inhibitors make poor cancer drugs?
Inhibitors of essential mitotic kinases exemplify this paradigm shift, but intolerable on-target toxicities in more prolific normal tissues have led to repeated failures in the clinic. Proliferation rates alone cannot be used to achieve cancer specificity.
How do you prevent cancer cells from dividing?
Stopping cell division is a logical idea in treating cancer and is being pursued by other research teams. A recent study by scientists from the University of Oxford, Uppsala University and Karolinska Institutet found that shutting down an enzyme called DHODH could stop cancer cells from dividing.
Do cancer cells form during mitosis or meiosis?
During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by certain genes. When mitosis is not regulated correctly, health problems such as cancer can result.
How does cancer treatment target the cell cycle?
Cell cycle checkpoints are essential to halt cell cycle progression in response to DNA damage, thereby allowing time for DNA repair. Inhibition of CHK1 or WEE1 in cancer cells prevents cell cycle arrest during S or G2 phase and enables cell proliferation despite accumulation of DNA damage.
What drugs are used to treat cancer?
Drugs that disrupt mitotic progression, which are commonly referred to as `anti-mitotics', are used extensively for the treatment of cancer. Currently, all such drugs that have been approved for clinical use target microtubules, with the taxanes and vinca alkaloids showing much success against a number of cancers. Taxol is commonly used in the treatment of breast and ovarian cancers, and vinca alkaloids, such as vincristine, are often used in combination therapies to treat haematological malignancies (reviewed by Jordan and Wilson, 2004 ). Investigating the effects of these agents on microtubule dynamics ( Box 1) has revealed much about their mechanism of action. The vinca alkaloids, which are a class of compounds that were originally isolated from Catharanthus roseus (madagascar periwinkle), interact with β-tubulin at a region adjacent to the GTP-binding site known as the vinca domain ( Rai and Wolff, 1996 ). Within a concentration range that blocks proliferation, the vinca alkaloids bind to tubulin at the plus-tip of microtubules. At the lower end of this range, this inhibits microtubule dynamics without altering polymer levels, whereas at higher concentrations, it induces microtubule depolymerisation ( Jordan et al., 1991 ). In both situations, mitotic spindle formation is disrupted, and cells therefore fail to complete a normal mitosis ( Jordan et al., 1991 ). At very high concentrations (above 10 μM) vinca alkaloids can induce the aggregation of tubulin into para-crystals; however, this does not occur at clinically relevant concentrations ( Jordan and Wilson, 1999 ).
Is cell culture a model system?
Cell culture as a model system for studying anti-mitotics. Despite extensive research, the mechanism by which anti-mitotic drugs cause cell death is still poorly understood ( Rieder and Maiato, 2004 ). Much of our understanding of the action of anti-mitotic drugs is based on work carried out using cell culture systems.
Does cyclin B1 degrade?
It now appears that, in mammalian cells exposed to anti-mitotic agents, cyclin B1 is still slowly degraded despite chronic activation of the SAC ( Brito and Rieder, 2006; Gascoigne and Taylor, 2008 ).
Does cell fate depend on mitotic drug?
Cell fate was found to depend on the anti-mitotic drug used and on its concentration, but not on the duration of mitotic arrest. Cell death was found to be caspase-dependent and could be inhibited by a pan-caspase inhibitor, which also extended the duration of mitotic arrest. Fig. 1. View large Download slide.
Can cells die in mitosis?
Cells might die directly in mitosis, or divide unequally to produce aneuploid daughter cells. Alternatively, cells might exit mitosis without undergoing division. In this case, cells might then die in interphase, arrest in interphase indefinitely or enter additional cell cycles in the absence of division. Fig. 1.
Is mitotic disruption an anti-cancer drug?
The clinical success of the microtubule toxins suggests that mitotic disruption is an effective anti-cancer strategy. However, although the development of anti-mitotic drugs that do not disrupt microtubule dynamics appears to have circumvented the problem of neurotoxicity, the issue of immunotoxicity remains unresolved. Preliminary data from the Ispinesib trials indicate that significant neutropenia is induced by the drug, which suggests that the use of this agent will be restricted in a similar manner to the currently used compounds ( Tang et al., 2008 ). As an alternative to anti-mitotic drugs, the mitotic kinase Aurora B is also being explored as an anti-cancer drug target. Rather than preventing mitotic progression, drugs that inhibit Aurora B cause premature mitotic exit in the presence of unaligned chromosomes and a failure of cytokinesis, which ultimately leads to cell death ( Keen and Taylor, 2004 ). As a `mitotic driver' rather than an inhibitor of mitotic progression, Aurora B inhibitors offer an alternative strategy to target dividing cells ( Keen and Taylor, 2009 ). However, Aurora B inhibitors are still cytotoxic agents that kill normal dividing cells in addition to cancer cells and, as such, they are expected to induce the myelosuppression that is typical of the traditional anti-mitotic agents.
Why do anti-mitotic drugs fail to work in patients with solid tumors?
Despite the moderately successful application of some anti-mitotic drugs in few hematopoietic malignancies, the question remains: why do these inhibitors fail to work in patients with solid tumors? One reason may be that AURKs and PLKs are expressed primarily during M phase and are significantly downregulated or totally absent in other stages of the cell cycle. The M phase accounts just for 2%–10% of the entire cell cycle, and, depending on the tumor type, the time its component cells spend in M phase is often less than 1% (mitotic index). Thus, only a very small fraction of tumor cells are undergoing mitosis at any one time, in line with the observation that, in vivo, human cancer cells double in number only once every few months or years. That all tumor cells in a patient divide rapidly is a misconception generated from the relatively short doubling times observed in vitro or in xenograft models ( Chan et al., 2012, Komlodi-Pasztor et al., 2012, Mitchison, 2012 ). It is possible then that as AURK and PLK1 inhibitors can only act on their targets during M phase, they fail in solid tumors where dividing cells are scarce but show some therapeutic index in blood cancers, where the malignant cells divide more frequently.
Why is the cell cycle important?
The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic.
What is the function of MPS1?
Mps1 is a dual-specificity kinase ( Lauzé et al., 1995) that is critical for the recruitment of SAC proteins to unattached kinetochores, mitotic checkpoint complex (MCC) formation , and thus APC/C inhibition. Mps1 is also required for chromosome alignment and error correction ( Abrieu et al., 2001, Maure et al., 2007, Tighe et al., 2008 ). Inhibition of Mps1 activity causes cells to prematurely exit mitosis with unattached chromosomes, resulting in severe chromosome mis-segregation, aneuploidy, and eventually cell death ( Colombo et al., 2010, Hewitt et al., 2010, Jemaà et al., 2013, Kwiatkowski et al., 2010 ). Mps1 is overexpressed in several human tumors, and higher levels correlate with worse prognosis ( Salvatore et al., 2007, Slee et al., 2014, Tannous et al., 2013) and may contribute to the survival and proliferation of aneuploid cells ( Daniel et al., 2011 ). On the basis of these findings, Mps1 is considered as one of the more promising drug targets for anti-cancer therapy and has led to an intense search for small-molecule inhibitors against this kinase. Mps1 inhibitors have been identified and are either under development ( Colombo et al., 2010, Hewitt et al., 2010, Jemaà et al., 2013, Kwiatkowski et al., 2010, Liu et al., 2015, Naud et al., 2013, Tardif et al., 2011) or have entered the clinic (BAY 1161909, ClinicalTrials.gov Identifier: NCT02138812; BAY 1217389 ClinicalTrials.gov Identifier: NCT02366949). Notably, inhibition of SAC signaling through Mps1 inhibitors provides the first indication of the feasibility of such an approach. Of interest, given the current understanding on the mechanism of action of SAC inhibitors, it has been suggested that they be used with MTAs that perturb proper chromosome alignment to enhance chromosome segregation errors above the threshold required to kill cancer cells. In support of this hypothesis, a reduction in Mps1 protein levels or chemical inhibition of Mps1 activity has been shown to sensitize cancer cells to taxol treatment ( Janssen et al., 2009 ).
What are the roles of Aurora Kinases A, B, C?
Aurora kinases A, B, and C (AURKA, B, C) play important roles in centrosome/centromere function and spindle assembly during mitosis. AURKA is involved early in mitosis by regulating centrosome maturation and disjunction, thereby playing a role in establishing a bipolar mitotic spindle ( Malumbres, 2011 ). AURKB is a component of the chromosome passenger complex (CPC), which contributes to SAC function at kinetochores by correcting faulty spindle attachments ( Kops et al., 2005, Lara-Gonzalez et al., 2012, Musacchio and Salmon, 2007 ), and also functions in cytokinesis ( Malumbres, 2011 ). Although the role of AURKC remains to be fully elucidated, functional redundancy with AURKB has been suggested based on its association with the CPC and the fact that AURKB loss of function can be rescued by AURKC ( Malumbres, 2011 ). Abnormal AURK activity is associated with defects in cell division and aneuploidy. AURKA is amplified in cancers of the breast, ovary, lung, bladder, stomach, pancreas, head-and-neck, and colon, whereas AURKB is overexpressed in breast cancer, NSCLC, glioblastoma, and prostate cancer ( Boss et al., 2009, Lens et al., 2010, Malumbres, 2011 ). A role for AURKC in tumorigenesis has yet to be described.
What is PLK4 in cancer?
PLK4 is a conserved key regulator of centriole duplication ( Bettencourt-Dias et al., 2005, Habedanck et al., 2005) and is aberrantly expressed in several human tumors ( Macmillan et al., 2001, Mason et al., 2014 ). Dysregulation of PLK4 expression causes loss of centrosome numeral integrity, which promotes genomic instability ( Basto et al., 2008, Ganem et al., 2009, Holland et al., 2010) but could also enable cancer cells to tolerate its effects. Further disruption of centriole duplication by inhibition of PLK4 activity could exacerbate the genomic instability in cancer cells and force their death. Notably, PLK4 is a versatile potential target that is also active outside of mitosis. Levels of PLK4 coincide with centriole duplication, low in G1 phase, increasing incrementally during S phase and reaching a maximum during G2/M phase. Thus, PLK4 inhibition may also affect G1 or S phase tumor cells that are largely refractory to the effects of mitosis-specific drugs. These findings point to PLK4 as a novel therapeutic target. Small molecules that inhibit the kinase activity of PLK4 have been identified ( Mason et al., 2014, Wong et al., 2015 ), and one of these inhibitors, CFI-400945 ( ClinicalTrials.gov Identifier: NCT01954316), is currently in phase I clinical testing. PLK4 has a synthetic lethal interaction with PTEN deficiency ( Brough et al., 2011 ), and increased preclinical activity for CFI-400945 is observed in PTEN-deficient compared to PTEN wild-type human cancer models, suggesting that PTEN deficiency may be a predictive biomarker of CFI-400945 response. Nuclear PTEN is required for DNA repair ( Bassi et al., 2013 ), and reduced expression of PTEN in human tumors correlates with increased genomic instability ( Bose et al., 2002, Puc et al., 2005 ). Thus, deregulation of centriole duplication and mitotic errors caused by CFI-400945 could increase the genomic instability in PTEN-deficient cells and enhance cell death.
What are the kinases that are involved in mitosis?
The never-in-mitosis Aspergillus (NIMA)-related kinases Nek2, Nek6, Nek7, and Nek9 are serine/threonine kinases that are involved in mitotic progression. Nek2 is required for centrosome separation and participates in establishing the bipolar spindle, whereas Nek9 activates Nek6 and Nek7 by phosphorylation to maintain spindle structure and function ( O’regan et al., 2007, O’Regan and Fry, 2009 ). Nek2 may have additional functions both in chromosome condensation ( Di Agostino et al., 2004) and in the SAC through its interactions with highly expressed in cancer-1 (Hec1, also known as Ndc80) and mitotic arrest deficient-1 (Mad1) ( Chen et al., 2002, Du et al., 2008, Lou et al., 2004, Wei et al., 2011 ). Like Nek2, Nek6, Nek7, and Nek9 have been implicated in centrosome separation ( Bertran et al., 2011 ). Nek2 and Nek6 are overexpressed in various human tumors ( Bowers and Boylan, 2004, Cappello et al., 2014, Nassirpour et al., 2010 ), and several cancer-associated Nek mutations have been identified ( Moniz et al., 2011 ). Nek2 siRNA inhibits the in vitro proliferation of human cancer cell lines, as well as that of xenografts generated by injection of these cells ( Kokuryo et al., 2007, Suzuki et al., 2010, Tsunoda et al., 2009 ). This depletion of Nek2 causes centrosomal abnormalities, aneuploidy, and cell-cycle arrest, which lead to cell death ( Cappello et al., 2014 ). Nek6 knockdown suppresses anchorage-independent growth and causes death in human cancer cell lines ( Nassirpour et al., 2010 ), while Nek6 overexpression inhibits p53-dependent cellular senescence ( Jee et al., 2010 ). In general, these findings suggest that Nek kinases are critical for MT organization and ensuring fidelity during mitosis and thus could be attractive targets for drugs that would be complementary to MTAs. Small-molecule inhibitors of Nek2 kinase activity have been identified ( Eto et al., 2002, Li et al., 2007, Meng et al., 2014, Rellos et al., 2007, Westwood et al., 2009 ), as well as a small molecule that disrupts the Hec1-Nek2 interaction ( Wu et al., 2008 ). Nek6 inhibitors have yet to be reported.
What is the target of mitotic fidelity?
Two other interesting targets with links to mitotic fidelity are microtubule-associated serine/threonine kinase-like (Mastl, also known as Greatwall [Gwl]) and haploid germ cell-specific nuclear protein kinase (Haspin, also known as germ cell-specific gene-2 [Gsg2]). Mastl acts as a regulator of mitotic progression by promoting the inactivation of the tumor suppressor protein phosphatase 2A (PP2A) associated with the B55δ regulatory subunit ( Castilho et al., 2009, Vigneron et al., 2009, Burgess et al., 2010 ). Inactivation of PP2A/B55δ during mitosis is required to keep cyclin B1/Cdk1 activity high. Mastl depletion results in severe mitotic defects that are likely the result of decreased cyclin B1/Cdk1 substrate phosphorylation. These defects include defective chromosome condensation, abnormal spindle assembly, and chromosome segregation errors ( Archambault et al., 2007, Bettencourt-Dias et al., 2004, Burgess et al., 2010 ). Thus, Mastl inactivation may cause lethal genomic instability in cancer cells. A role for Mastl in recovery following DNA damage has also been reported, suggesting that inhibition of Mastl could be beneficial in DNA damage-based therapies ( Peng et al., 2010 ). Mastl upregulation occurs in various types of human cancer and correlates with aggressive clinicopathological features ( Wang et al., 2014 ). Specific inhibitors of Mastl have not been identified to date and will be useful to further understand the biology of this potential target.
Why are MTAs used in mitosis?
Although MTAs are developed to selectively target actively dividing cells by virtue of the intense turnover and restructuring of spindles during mitosis, interphase cells may be targeted too, as microtubules are prevalent throughout the cell-cycle.
What is mcle1 in mitosis?
Mcl1 is gaining traction as an antimitotic target with increasing evidences associating its degradation in mitosis to the timely induction of cell death. 49 As a member of the Bcl-2 family of anti-apoptotic proteins, Mcl1 is able to disrupt Bax and Bak’s interaction with the mitochondrial membrane, thereby averting apoptosis initiation. The expression of Mcl1 peaks when a cell is arrested in mitosis either normally (possibly to resolve checkpoint errors) or drug-induced. The apoptotic suppression by Mcl1 is not permanent, as it undergoes a concerted sequence of phosphorylation–polyubiquitination, culminating in APC Cdc20 dependent degradation by the proteasome. 50 Because of this transient protection, arrested cells will escape death if the cyclin B’s level drops to the exit threshold before Mcl1 is degraded sufficiently to elicit apoptotic responses. Studies have shown that Mcl1 is overexpressed in patient-derived tumors. 51, 52 Regulatory proteins such as protein phosphatase PP2A and deubiquitinase USP9X along the Mcl1 axis have been proposed as a possible intervention point, inhibition of which will promote the degradation of Mcl1 and abolish its cytoprotectivity. 53 This strategy could probably boost clinical efficacy in combination with other mitosis-specific therapeutics.
How do tumor cells differentiate from non-dividing cells?
From the perspective of tumor cells, one key distinction that separates them from the non-dividing cells in the body is that they undergo unrestricted growth. Perhaps not in terms of proliferation rate (especially when compared to normal dividing cells), but for them to grow, they need to divide. This crudely covers the issue of selectivity to a certain extent and confers vulnerability during cellular division, thus making mitosis a valid point of intervention in anti-cancer therapy. It is widely regarded that antimitotics cause prolonged mitotic arrest due to the activation of SAC. Following mitotic arrest, the cells can die from MCD or adopt different cell fates. 7 A repertoire of chemical inhibitors targeting various mitosis-specific kinases, motor proteins and multiprotein complexes has been developed since the relative success of the classical microtubule poisons. These drugs are naturally more mitosis-selective yet without the side effect of neurotoxicities. However, dramatic bench results do not necessarily translate to bedside efficacy, as seen in a majority of these mitotic therapeutics. The inherent slow growth of human tumors and the rapid development of drug resistance (associated to mitotic slippages both as a cause and as a consequence) limit patients’ response and curb the full potential of existing mitosis-selective inhibitors. As such, much work is needed to map out the complexities of how cytotoxic drugs work as medicine, to harness the full potential of antimitotics, and to resolve the gaps behind preclinical to clinical shortcomings. Identifying new cancer-specific druggable molecules, optimizing combinatorial treatments and devising novel anticancer strategies remain a future challenge and hope for treating cancer.
What is the theme of anticancer therapy?
The general theme afflicting the development of anticancer therapeutics has always been the inability of high-potential drugs to deliver their efficacy in human trials. These drugs are envisioned to recapitulate the success of MTAs by disrupting mitosis to induce prolonged arrest and cell death, without the ill effects of myelosuppression and neurotoxicities. The question remains, why aren’t they working like they are supposed to?
What are checkpoint kinases?
Checkpoint kinases 1 and 2 (Chk1 and 2) are DNA damage checkpoint proteins regulating p53 and Cdc25 to mediate cell-cycle arrest/apoptosis and Cdk1 activation, respectively. 15 As G2 checkpoints, they are important for ensuring cells with cellular damage are prevented from progressing into mitosis until the damage is repaired. Studies have shown that the inhibition of checkpoint genes promote DNA damage-induced MCD. 16, 17 Following that, a host of Chk1 inhibitors have been identified and tested for clinical efficacy ( Table 1 ). However, side effects and limited responses plague single-agent therapies using these drugs.
Do antimitotics target the death pathway?
Current antimitotics do not aim at the death pathway directly. Rather, intracellular stresses induced during mitotic arrest had been proposed to collectively orchestrate the cell’s demise. How this is conducted remains poorly understood. In addition, it is also unknown how chromosomal DNA damage 54 (often observed in cancer cells treated with chemical agents) can occur on a highly condensed chromosomal structure. Recently, we had identified a novel molecular event directly linking the regulation of condensin to mitotic death. 55 Our model shows that caspase-3-mediated depletion of the condensin 1 subunit Cap-H and the subsequent loss of chromosomal structural integrity is crucial in MCD. Clearly, these early results require validation for their importance in cancer therapy. Still, condensin-based approaches may be an interesting avenue to devise novel anticancer strategies. Although targeting condensin may not be an orthodox approach given that it is not cancer-specific, it is worth noting that the bulk of condensin’s activities abound during mitosis. Condensins are required for proper chromosome assembly, contributing towards condensation and metaphase chromosomal architecture and chromosome segregation in vertebrate cells. 56 Although condensin has also been implicated to regulate higher-order chromosome structure during interphase, studies on condensin perturbation reveal that aberration occurs predominantly during chromosomal condensation and mitotic progression. 57 Hence, targeted inhibition of condensin will generally affect only dividing cells.