Antimitotic drugs in cancer chemotherapy: Promises and pitfalls
Isabel Marzo *, Javier Naval
Departamento de Bioquimica y Biologia Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Spain
1. Currently used antimitotic drugs in cancer chemotherapy
Although cell behavior is quite heterogeneous among different
types of tumors, and even among patients, a frequent feature of
tumor cells is the increased rate of proliferation when compared to
normal cells. This capacity is usually a consequence of unrespon￾siveness to growth inhibitory signals, self-sufficiency in growth
factors or both [1]. Moreover, some of the compounds used in
cancer chemotherapy that were initially identified in unbiased
screening have lately been shown to act by blocking mitosis and
subsequently inducing cell death. Vinca alkaloids and taxanes are
the two groups of anticancer drugs targeting mitosis which are
currently in use for the treatment of a variety of tumors including,
breast cancer, lung cancer, neuroblastoma, rhabdomyosarcoma,
acute leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma.
Although these two families of compounds have different chemical
structure and origin, all of them bind to b-tubulin and disturb the
dynamics of microtubules. Reorganization of microtubules is a
critical event during mitosis, orchestrating the relocalization of
centrosomes and the correct segregation of sister chromatids in
daughter cells. Vinca alkaloids (vincristine, vinblastine, vindesine
and vinorelbine) prevent the polymerization of microtubules,
while taxanes (paclitaxel and docetaxel) stabilize pre-existing
microtubules, what also impedes the formation of the mitotic
spindle. Recently, a new family of microtubule-targeting com￾pounds, the epothilones, have been developed and approved for
taxane-resistant breast tumors. A significant concern about anti￾microtubule agents (MTA) is that these compounds cause
significant side effects such as neutropenia and neurotoxicity.
Loss of neutrophils is a consequence of the toxicity of MTA on
dividing precursor cells and neurotoxicity is probably related to
the critical role of microtubule turnover in neurons. However, the
major inconvenience in using MTAs in chemotherapy is their
limited efficacy as single agents. These limitations prompted the
search for more specific mitosis-targeting drugs, with enhanced
therapeutic potency and fewer side effects. Mitosis-specific
kinases and microtubule-motor proteins were identified as
potential drug targets and accordingly several inhibitors have
been developed in the last years.
2. The promises: preclinical data on mitosis-targeting drugs
2.1. Cdks and Chks inhibitors
Cyclin-dependent kinases and checkpoint kinases control
transitions during cell cycle phases (Fig. 1). Cyclin-dependent
kinase 1 (Cdk1) regulates cell entry into mitosis by phosphorylat￾ing several proteins that orchestrate different aspects of cell
division, such as chromosome condensins, nuclear lamins,
centrosome and microtubule-associated proteins and Golgi matrix
proteins. Other Cdks are activated at different stages of cell cycle
and their activity is required for G1/S or G2/M transitions. On the
other hand, checkpoint kinases are activated in response to DNA
damage to arrest cell cycle progression until the damage is
repaired. Two of the first Cdk or Chk inhibitors proposed for cancer
treatment were UCN-01 and flavopiridol (alvocidib). UCN-01 is a
staurosporine analog (7-hydroxystaurosporine) that indeed
Biochemical Pharmacology xxx (2013) xxx–xxx
A R T I C L E I N F O
Article history:
Received 14 May 2013
Accepted 11 July 2013
Available online xxx
Keywords:
Mitosis
Cancer
Chemotherapy
A B S T R A C T
Cancer cells usually display higher proliferation rates than normal cells. Some currently used antitumor
drugs, such as vinca alkaloids and taxanes, act by targeting microtubules and inhibiting mitosis. In the
last years, different mitotic regulators have been proposed as drug target candidates for antitumor
therapies. In particular, inhibitors of Cdks, Chks, Aurora kinase and Polo-like kinase have been
synthesized and evaluated in vitro and in animal models and some of them have reached clinical trials.
However, to date, none of these inhibitors has been still approved for use in chemotherapy regimes. We
will discuss here the most recent preclinical information on those new antimitotic drugs, as well as the
possible molecular bases underlying their lack of clinical efficiency. Also, advances in the identification of
other mitosis-related targets will be also summarized.
2013 Elsevier Inc. All rights reserved.
* Corresponding author at: Dept. Bioquı´mica y Biologı´a Molecular y Celular,
Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
Tel.: +34 976 762 301.
E-mail address: [email protected] (I. Marzo).
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inhibits Cdk1/2, Chk1/2 as well as protein kinase C (PKC) (Table 1).
UCN-01 has been shown to be an abrogator or the G2 checkpoint
[2] and to induce apoptosis in cells of different origin [3,4].
Flavopiridol, a synthetic flavonoid based on plant extracts, was the
first Cdk inhibitor to enter clinical trials (see point 3), two decades
ago, but it has not yet been approved for use in the clinic due to its
low antitumoral activity as a single agent in vivo [5].
P276-00 was identified as a selective and potent Cdk4 inhibitor
that induces apoptosis in cell lines and synergizes with doxorubi￾cin in xenograft models [6]. Other molecules have been described
to inhibit Cdks and Chks and could in the future enter clinical trials.
The Cdk and Erk5 inhbitor TG02 exhibits anti-myeloma activity on
cell lines, patient plasma cells ex vivo and in mouse xenograft
models. Moreover, TG02 enhanced the toxicity of bortezomib and
lenalidomide in myeloma [7]. Sangivamycin-like molecule 6
(SLM6), an inhibitor of Cdk9, has only been tested in myeloma
cells, showing higher activity than flavopiridol [8]. VMY-1-103 is a
dansylated analog of purvalanol B that induces cell cycle arrest and
apoptosis by inhibiting Cdk1 and also by disrupting the mitotic
spindle apparatus [9].
2.2. Aurora A and B inhibitors
Aurora Ser/Thr kinases are critically involved in the control
of mitosis (Aurora A and Aurora B) and meiosis (Aurora C).
Aurora A localizes at the centrosome in early G2 phase and
controls mitotic entry and bipolar spindle assembly (Fig. 1).
Aurora B is the catalytic component of the ‘chromosomal
passenger complex’ (CPC). In human cells, Aurora B could have
up to 40 substrates related to kinetochores [10]. Phosphor￾ylation of these substrates by Aurora A controls chromosome
structure, cohesin removal, mitotic spindle formation, kineto￾chore assembly, correction of defective chromosome-spindle
attachments and shortening of segregating chromosomes
(Fig. 1). Thus, inhibition of Aurora A perturbs mitosis and
can provoke mitotic arrest or chromosomal instability
followed, in many cases by cell death [11]. This, together
with the fact that Aurora kinases are frequently overexpressed
in cancer cells [12], prompted the development of small
aurora kinase inhibitors as potential anticancer agents. A large
number of this kind of molecules have been developed in the
last years (Table 1). Many of these compounds bind to the ATP
cassette of aurora kinases and inhibit the three known
proteins of the family as well as other non-mitotic kinases.
Besides showing apoptotic activity, aurora kinase inhibitors
have been reported to synergize with other antitumor drugs
[11] and these promising preclinical results led some of these
compounds to enter clinical trials (Table 2). Other compounds,
such as ZM447439 and JNJ-7706621 are still under preclinical
research (Table 2).
Fig. 1. Mitotic proteins as antitumor drug targets. Mitosis is a complex process requiring the step-wise participation of several regulatory proteins. Some of these proteins
have been proposed to be relevant drug targets for antitumor therapies (red boxes) and accordingly protein inhibitors are in preclinical development and being tested in
clinical trials. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
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Table 1
Antimitotic agents in clinical trials.
Stage Combinations in trial Main targets References
Cdk and Chk inhibitors
Flavopiridol (Alvocidib) II Radiation, gemcitabine, oxaliplatin,
fluorouracil, leucovorin, doxorubicin,
irinotecan, vorinostat,
lenalidomide, docetaxel,
cyclophosphamide, rituximab,
cisplatin, trastuzumab, cytarabine,
mitoxantrone, fludarabine,
depsipeptide, imatinib, velcade,
carboplatin
Cdk1, Cdk2, Cdk4, Cdk6, Cdk7 and Cdk9 [65]
UCN-01 II Carboplatin, irinotecan, cytarabine,
perifosine, gemcitabine, topotecan,
cisplatin, fluorouracil, prednisone,
leucovorin, fludarabine,
Cdk1, Cdk2, Chk1, Chk2 and PKC [2,3,4]
PD-0332991 (palbociclib) II Tamoxifen, Velcade, dexamethasone,
anastrozole, letrozole, cytarabine,
mitoxantrone, paclitaxel
Cdk4 and Cdk6 [33,34]
SCH727965 (Dinaciclib) III MK2206, Velcade, dexamethasone,
epirubicin, ofatumumab, paclitaxel,
rituximab
Cdk1, Cdk2, Cdk5 and Cdk9 [66]
P276-00 II Gemcitabine, radiation, carboplatin Cdk1, Cdk4 and Cdk9 [6]
AZD7762 I Gemcitabine, irinotecam Chk1 and Chk2 [67]
AT7519 II Velcade Cdk2, Cdk4, Cdk5 and Cdk9 [30]
PF-477736 I Gemcitabine Chk1 and Chk2 [68]
XL844 (EXEL-9844) I Gemcitabine Chk1, Chk2, VEGFR2/3, FLT3 and PDGFR. [69]
Roscovitin (Seliciclib) II Doxorubicin, sapacitabine Cdk1, Cdk2, Cdk5, Cdk7 and Cdk9 [31]
R547 I – Cdk1, Cdk2, Cdk4 and Cdk7
SNS-032 I – Cdk2, Cdk7 and Cdk9 [29]
BAY 1000394 II Etoposide, cisplatin, carboplatin Cdk1, Cdk2, Cdk3 and Cdk4 [70]
Aurora kinase inhibitors
MLN8237 (Alisertib) II Paclitaxel, rituximab, vincristine,
erlotinib, vorinostat, velcade,
abiraterone, prednisone, irinotecan,
temozolomide, pazopanib,
Aurora A [11,35–37]
AZD1152 (Barasertib) III Cytosine arabinoside, Aurora B [38,39]
VX-680 (Tozasertib) II – Aurora A, Aurora B, Aurora C, Src, GSK3b, JAK2 and BCR-Abl. [40,41]
ENMD-2076 II – Aurora A [42]
AT-9283 II – Aurora A, Aurora B, JAK2/3, STAT3, BCR-Abl, Tyk2 and VEGF. [44]
Danusertib (PHA739358) II – Aurora A, Aurora B, Aurora C, BCR-Abl, FGFR1, FL3 and other kinases [43]
AS703569 I Gemcitabine Aurora A, Aurora B and Aurora C, BCR-Abl, Akt and other kinases
AMG-900 I – Aurora A, Aurora B and Aurora C [71]
MLN8054 I – Aurora A [72]
BI811283 II Cytarabine Aurora B
KW2449 I – Aurora A [73]
VX-689 I Docetaxel Aurora A [74]
PF-03814735 I – Aurora A and Aurora B [45]
GSK1070916 I – Aurora B and Aurora C [75]
CYC116 I – Aurora A, Aurora B, Aurora C, FLT3 and VEGFR-2
SNS-314 I – Aurora A, Aurora B and Aurora C [76]
Polo like kinase inhibitors
ON01910.Na (Rigosertib) II Irinotecan, oxaliplatin, gemcitabine, Plk1,Also PI3K inhbitor. Non ATP competing [46]
BI6727 (Volasertib) II Cytarabine, pemetrexed, cisplatin,
carboplatin, BIBF1120, afatinib,
[47]
BI2536 II – [54]
GSK461364 I – [48]
NMS-1286937 I –
TAK-960 I – [77]
Mitotic kinesin inhibitors
Ispinesib II Capecitabine, carboplatin, docetaxel Eg5 [49,50]
ARRY-520 II Velcade, dexamethasone, carfilzomib Eg5 [51]
AZD4877 II – Eg5 [52]
SB-743921 II – Eg5 [53]
LY2523355 II Eg5
ARQ 621 I – Eg5
MK-0731 I – Eg5 [78]
4SC-205 I – Eg5
GSK923295 I – CENP-E [79]
Other targets
MK1775 II Gemcitabine, cisplatin, carboplatin, 5-
fluorouracil, temozolomide, topotecan,
paclitaxel,
Wee1
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2.3. Polo-like kinase 1 inhibitors
Polo-like kinase 1 (Plk1) is a Ser/Thr kinase involved in the
activation of CDK1/cyclin B, in centrosome maturation, and also in
spindle assembly and cytokinesis [12] (Fig. 1). Overexpression [13]
and point mutations of Plk1 [14] have been described in tumor
cells. Ablation of Plk1 by RNA interference techniques induces cell
cycle arrest and death [15]. Small molecule inhbitors of Plk1 have
also been described to induce growth inhibition and cell death in
vitro and to reduce tumor growth in xenograft models [15,16]. Due
to encouraging preclinical data, some Plk1 inhibitors have entered
clinical trials and two of these compounds have reached Phase III
stage (Table 1). The first results of these clinical trials will be
discussed later.
2.4. Inhibitors of motor proteins
Microtubule-driven motor proteins participate in key
events of mitosis and cell division. So far, sixteen kinesins
have been implicated in different events of mitosis and
cytokinesis [17]. Among these, Eg5 (KSP, KIF11) and CENP-E
have emerged as potential drug targets for antitumor
treatment. Eg5 binds to antiparallel spindle microtubules
and push them apart by moving toward plus ends (Fig. 1).
This movement is essential for the formation of the bipolar
spindle. Thus, inhibition of Eg5 impedes correct assembly of
the mitotic spindle, activating the spindle checkpoint and
provoking mitotic arrest that can lead to cell death. Based
in these facts, Eg5 was proposed as a target for antitumor
chemotherapy. Small molecule inhibitors were identified and
analyzed at the preclinical level [18–21] and a few of them
have entered clinical trials (Table 1). Apart from Eg5, CENP￾E could be a suitable anticancer drug target. This large
kinesin is essential for chromosome congression and
alignment during the metaphase-anaphase transition. A
CENP-E inhibitor (GSK923295) has shown antitumor activity
in vitro and in xenograft models [18]. Other mitotic kinesins,
like HSET or MCAK, could emerge in the future as drug
targets [17].
2.5. Inhibitors of other proteins implicated in mitosis
Mitosis is a very complex process that requires a tight
regulation and control. Many proteins, apart from microtubules,
Cdks, Chks, Plk1 and kinesins participate in different stages of
mitosis and cytokinesis (Fig. 1). One of these proteins is survivin,
a dual function member of the IAP (Inhibitor of Apoptosis
Protein) family. During mitosis, survivin localizes at the mitotic
spindle and interacts with microtubules. Interestingly, survivin
is highly expressed in tumor cells and could be a target for
anticancer therapies [22]. This hypothesis is supported by the
fact that the survivin suppressant YM155 induces cell death and
sensitizes tumor cells to other cytotoxic agents [23]. A 16-mer
locked nucleic acid (LNA) oligonucleotide targeting survivin
mRNA, SPC3042, has shown to have apoptotic activity and to
sensitize prostate cancer cells to taxol [24]. The kinase Haspin
phosphorylates Histone 3 at Thr3, an event necessary for mitosis
progression. Two small molecules that inhibit Haspin, 5-ITu [25]
and CHR-6494 [26], have been recently discovered. CHR-6494
induces cell death in HCT-116, HeLa and MDA-MB-231 cells and
shows antitumoral activity on HCT-116 xenografs in nude mice
[26]. Mps1 is a kinase required for the activation of the spindle￾assembly checkpoint (SAC) and inhibitors of this protein are
currently under research for their possible antitumor activity
(Table 2). Other antimitotic drugs under development target the
Wee1 protein kinase, an inhibitory regulator of the G2/M
checkpoint through phosphorylation and inactivation of Cdk1.
MK1775 [27] and PD0166285 [28] are small molecule inhibitors
of Wee1 and the first is being tested in clinical trials in
combination with anticancer drugs.
3. Results of clinical trials
3.1. Chk and Cdk inhibitors
First antimitotic compounds to enter clinical trials were
flavopiridol and UCN-01, in the late 90s. Since then, at least 60
trials of flavopiridol and UCN-01 have been conducted
(www.clinicaltrials.gov). In some cases combinations with other
compounds were evaluated (Table 1). These combinations
included agents that induce DNA damage (oxaliplatin, cisplatin,
carboplatin, doxorubicin, irinotecan, mitoxantrone), nucleoside
analogs (gemcitabine, fluorouracil, cytarabine, fludarabine),
histone-deacetylase (HDAC) inhibitors (vorinostat), antimicro￾butule drugs (docetaxel, paclitaxel), immunomodulators (lena￾lidomide), antibodies (trastuzumab, rituximab), proteasome
inhibitors (bortezomib) and kinase inhibitors (imatinib). In
general, only very limited responses were observed in most of
these studies [5,29–31]. Yet, some encouraging data have been
recently published, mainly in the treatment of hematological
malignancies. In a recent report, a 67% complete remission (CR)
was found in patients with newly diagnosed AML after
treatment with flavopiridol/cytarabine/mitoxantrone [32]. One
complete remission and two partial responses were also
observed in mantle cell lymphoma patients with the Cdk4/6
inhibitor PD0332991 [33]. This compound also showed activity
in liposarcoma treatment [34]. A number of clinical trials on
some compounds are ongoing, still holding promise on the
success of these targeted therapies.
3.2. Aurora kinase inhibitors
The first clinical trials with aurora kinase inhibitors were
launched in 2005. At least seventy trials have been initiated to
evaluate the clinical activity of different aurora kinase inhibi￾tors. The largest number of studies corresponds to alisertib and
Table 2
Antimitotic agents in preclinical development.
Compound Target References
TG02 Cdk1, Cdk2, Cdk9 and Erk5 [7]
VMY-1-103 Cdk1 [9]
SLM6 Cdk9 [8]
CDKI-71 Cdk9 [80]
BMK-Y101 (Ibulocydine) Cdk7 and Cdk9 [81]
Chir-124 Chk1
Purvalanol A Cdks and c-Src [82]
ZM447439 Aurora A and Aurora B [83]
JNJ-7706621 Aurora A, Aurora B and Cdks
TC-28 Plk1
Poloxin Plk1 [84]
GW843682X Plk1 [16]
ZK-Thiazolidinone Plk1
LFM-A13 Plk1
S-Trityl-L-cysteine (STLC) Eg5 [85]
Dimethylenastron Eg5
K858 Eg5
Monastrol Eg5 [86]
EMD534085 Eg5
YM155 Survivin [87]
SPC3042 Survivin
5-ITu Haspin [25]
CHR-6494 Haspin
NMS-P715 Mps1 [88]
MPI-0479605 Mps1 [89]
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barasertib (Table 1). A total of 34 Phase I/II trials with alisertib,
as a single drug or in combination with others, have been
registered at the official site www.clinicaltrials.gov. Seven trials
have been completed and the results of three studies have been
recently published. In a trial with platinum-resistant or refractory
gynecological tumors only short-term responses were attained in
3 out of 31 patients [35]. In a Phase I study in advanced solid
tumors, a partial response lasting more than one year was
reported [36] and stable disease was the best response in another
trial in advanced solid tumors [37]. There are still not data on trials
using combinations of alisertib and chemotherapeutic drugs. The
Aurora B inhibitor barasertib is currently being assayed in a Phase
III trial in combination with low dose cytosine arabinoside
(Table 1). Three studies of AZD1152 (barasertib) as a single agent
in acute myeloid leukemia (AML) [38] have reported responses in
19–25% of the patients, warranting further assays in this
pathology and probably other hematological malignancies.
However, solid tumors do not seem to respond to barasertib
[39]. The pan-aurora inhibitor VX-680 (MK-0457, tozasertib) has
showed activity against refractory leukemia [40]. The activity of
VX-680 on BCR-Abl+ leukemia could be related to its ability to
inhibit this kinase (Table 1). Stable disease in half of the patients
with solid tumors was the best response in a Phase I trial [41].
Other completed trials with aurora kinase inhibitors have yielded
similar results [42–45].
3.3. Plk1 inhibitors
Although being discovered more recently than Cdk, Chk or
Aurora kinase inhibitors, some Plk1 inhibitors have already
entered clinical trials and results of a few of them are available.
Many of these inhibitors are drugs that compete with ATP for the
substrate binding site. Rigosertib (ON01910.Na) has been
included in 23 trials (www.clinicaltrials.gov). The results of
four of these studies have shown promising antitumoral activity
of this compound, alone or combined with gemcitabine [46]. The
only work reporting clinical activity of volasertib (BI6727)
demonstrated limited efficacy of this compound when used as a
single agent against advanced solid tumors [47]. Nevertheless,
forthcoming results of completed or ongoing studies in
combination with different chemotherapy drugs could be more
positive. In the only study with GSK461364, stable disease was
the best response observed in solid tumors [48]. A non ATP￾competing kinase inhibitor in development is poloxin, a
derivative of thymoquinone, a phytochemical from Nigella
sativa. Poloxin is the first Polo-box domain inhibitor of Plk1
[49] and could serve as a starting point to develop bifunctional
inhibitors.
3.4. Mitotic kinesin inhibitors
Near twenty studies have analyzed the clinical efficacy of the
Eg5 inhibitor ispinesib (www.clinicaltrials.gov). Unfortunately,
this agent has demonstrated lack of, or very modest, activity
[50,51] and no more trials are currently active. The development of
ARRY-520 for leukemia [52] and AZD4877 in urothelial cancer [53]
has been halted also due to lack of clinical activity. Stable disease
was observed in a cholangiocarcinoma patient in a Phase II trial
with SB-743921 [54].
3.5. Wee1 inhibitor
The preclinical activity of MK1775 prompted initiation of
clinical trials, two of which have been terminated (www.clinical￾trials.gov) with no results published to date. The other six trials are
still active.
4. The pitfalls: which could be the molecular basis for the
failure of antimitotics?
Despite promising preclinical results, many of the selected
antimitotic drugs have not shown to be very effective in clinical
trials. Many can be the reasons for this limited activity. In some
cases, cell resistance caused to overexpression of efflux pumps can
prevent accumulation of the drug inside tumor cells. A recent work
has demonstrated that the low activity of the Plk1 inhibitor BI2536
could be explained by its low accumulation inside tumors [55].
However, although some of the new compounds are not substrates
of the P-glycoprotein, they do not exhibit a high activity against
tumor cells. Especially striking was the failure of kinesin motor
inhibitors. It has been proposed that the kinesin KIF15 could
substitute for Eg5, allowing cells to surpass the effect of Eg5
inhibitors [17].
Two recent reviews have proposed that the low mitosis rate in
tumors in vivo could be behind the limited activity of anti-mitotic
compound observed in clinical trials [5,56]. This hypothesis
implies that the success of ‘‘classical’’ MTA could be based not
only in the inhibition of mitosis, but also in the toxicity on
interphase cells. Paradoxically, then, the cause of MTA side effects
would also be the reason of their effectiveness against tumor cells.
In this sense, more targeted antimitotic drugs, would be less toxic
to normal cells but also to non-mitotic tumor cells. In any case,
even if tumor cells divide in vivo at lower rates than cell lines, they
present higher proliferative potential than non-tumor cells and
efficient antimitotic therapies should contribute to eliminate
tumors in combination with drugs targeting other processes, such
as cell signaling or apoptosis.
Itis widely accepted that antimitotic chemotherapeutics induce
a prolonged arrest of cells in G2/M phase that ultimately triggers
cell death. Full characterization of the mechanism linking both
events would be necessary in order to understand why some
tumors are refractory to these drugs. Another cause for the low
responses observed with antimitotic compounds could a process
known as ‘‘mitotic slippage’’, that occurs when cells escape from
mitotic arrest [57]. Mitotic slippage can be caused by a defective
SAC, but it also occurs in cells with proficient SAC when gradual
degradation of cyclin B1 allows for activation of the APC/C
(Anaphase Promoting Complex/Cyclosome). Mitotic slippage can
also be a consequence of a defective link between mitotic arrest
and cell death pathways. After exiting prolonged mitotic block,
cells can follow different fates [58]. Some cells will activate cell
death mechanisms and will die. Others enter a senescent state and
other cells will be able to enter a new division cycle. A very recent
work has demonstrated, in Drosophila melanogaster, that a
defective SAC combined with impaired apoptotic machinery can
lead to tumorigenesis [59]. These findings could explain why
therapies that target mitosis are not effective in some tumors. It
should also be bear in mind that some tumors display a great
heterogeneity and probably some cells with defects in SAC and/or
apoptosis could be spared by the treatment and originate
secondary tumors.
Advances in the last years suggest that the connection between
mitotic arrest and cell death signaling could depend on the activity
of mitotic kinases. Phosphorylation of Mcl-1, Bcl-xL and Bcl-2 [60]
has been reported to regulate cell death induced by diverse
antimitotic agents. Special interest has been focused on the role of
the antiapoptotic protein Mcl-1 whose degradation during mitotic
arrest has been shown to depend on Cdk1 activity [61,62] and later
proteosomal degradation. Recently, it has been described that
phosphorylation of FADD mediated by Plk1 and Aur-A is needed for
taxol-induced cell death [63]. Thus, antimitotic agents that target
mitotic kinases could be at the same time delaying the onset of cell
death by affecting the levels and activity of apoptosis regulators. In
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addition, combination with compounds targeting cell death
pathways could be a strategy to increase the activity of antimitotic
drugs.
Crosstalk with other cellular processes could underlie the
apparent resistance to some antitmitotics. For instance, autophagy
is a protective process that could also contribute to tumor
resistance to some antimitotic compounds. Zou et al. [64] have
demonstrated that the Aurora A inhibitor VX-680 activates
autophagy in breast cancer cells and repression of autophagy
sensitizes cells to VX-680 induced apoptosis [64]. These results
suggest that the activity of some antimitotic agents could be
increased by combining them with autophagy inhibitors.
5. Concluding remarks
So far, novel antimitotic agents have shown limited efficacy in
clinical trials and classical antimicrotubule drugs are still the best
approach in targeting mitosis to fight cancer. Nevertheless, several
clinical trials are still ongoing and could yield better results,
especially those combining antimitotics with other antitumoral
drugs. The development of bifunctional inhibitors that combine
the high binding affinity of ATP inhibitors with the specificity of
competitive inhibitors has been suggested as a strategy to increase
the efficacy of mitosis-targeting therapies [49]. The identification
of new protein targets could be another way to find efficient
antimitotic molecules to fight cancer. In this sense, future work on
the search for new antimitotic compounds and the rational design
of combination therapies would require a better understanding of
the links between mitosis alterations and cell death.
Acknowledgements
This work was supported by grants from Ministerio de Ciencia e
Innovacio´n (SAF2010-14920) and Gobierno de Arago´n/Fondo
Social Europeo (B16).
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