Introduction
Natural products are excellent sources for drug discovery and development. For cancer
therapy, many anticancer agents used in the clinic are either natural products or
derivatives from natural sources including plants, animals and microorganisms (also
of marine origin). For example, vincristine, irinotecan, etoposide and paclitaxel
are plant-derived compounds; actinomycin D, mitomycin C, bleomycin, doxorubicin and
l-asparaginase are drugs coming from microbial sources, and citarabine is the first
drug with a marine origin [1], [2]. In the past 50 years of war against cancer, these natural products have saved or
prolonged the lives of millions of cancer patients. However, most of these natural
products are cytotoxic agents targeting nonspecific targets expressed by both cancer
cells and, to a lesser extent, by normal proliferating cells. Therefore, the use of
these agents has been limited by their lack of selectivity between cancer cells and
normal cells. Furthermore, with the development of targeted cancer therapies using
monoclonal antibodies and synthetic protein kinase inhibitors since the late
1990s, cytotoxic natural products have gradually fallen out of fashion. As a result,
no novel category of natural products for the treatment of cancer was approved by
the FDA from 1997 to 2006. Nevertheless, the advancement of targeted therapies has
been slow and is still not able to meet the large and urgent need for novel cancer
therapy agents, especially for solid tumors. Therefore, recently, natural products
have become attractive again as one of the most important sources of innovative drugs.
In 2007, two natural products, ixabepilone and temsirolimus, were approved by the
FDA for cancer therapy. These facts suggest a possible new wave of natural products
in oncology [3].
In the present review, we will focus on microtubule-binding natural products used
for cancer therapy. Microtubules have been and will still be one of the important
targets for future cancer drugs because of their distinct roles in cell division and
universal presence in all eukaryotic cells. Microtubule-binding natural products,
including Vinca alkaloids and taxanes, have been the most commonly prescribed anticancer therapies
for decades. Many of these drugs remain among the most widely prescribed today for
the treatment of cancer. Furthermore, one of the newly approved anticancer natural
products in 2007, ixabepilone, is also a microtubule-binding agent. A number of microtubule-targeting
natural products are still in clinical trials. In this review, the microtubule and
the general anticancer mechanism of microtubule-binding agents are introduced. Then,
representative microtubule-binding natural products with anticancer effects are reviewed.
These natural products are classified according to their binding sites on the microtubule,
i.e., the colchicine-binding site, the Vinca alkaloid-binding site, the taxane-binding site or other binding sites. For each
class of natural products, information provided to show its development includes the
natural source of isolation, chemical structure characteristics, potent synthesized
analogues, mechanism of microtubule-binding and anticancer effects, and others. By
analyzing the development of microtubule-binding natural products, it might be possible
to clarify directions for future development of this kind of anticancer agent. Published
papers related to the topic of present review were searched in Pubmed using key words
such as “microtubule and cancer” and more specific ones like “taxanes”. References
were included or excluded based on the type of papers, time of publication and citation
rates. Generally, reviews and recently published research papers with high citation
rates were used for the present review.
Microtubule-Binding Reagents and their Mechanisms in Cancer Therapy
Microtubule-binding reagents
Since microtubule dynamics play an indispensable role in cell division, cell motility,
cellular transport, cell polarity and cell signaling, the microtubule appears as a
highly attractive target for anticancer drug design. An increasing number of antitumor
drugs target microtubules and exhibit their anticancer activities by altering the
polymerization dynamics of microtubules, disrupting mitosis, and thus inhibit cell
proliferation and induce apoptosis. In fact, in view of the success of this class
of drugs, it has been argued that microtubules represent the single best cancer target
identified to date and microtubule-targeted drugs might continue to be an important
chemotherapeutic class of drugs [8], [9].
Generally, on the basis of their effects on microtubule assembly at high concentrations,
microtubule-binding agents are usually divided into two distinct categories: microtubule-stabilizing
and microtubule-destabilizing agents. Microtubule-stabilizing agents stabilize tubulin
polymers by initiating tubulin polymerization as well as hyper-stabilizing existing
microtubules under normally destabilizing conditions. Microtubule-destabilizing agents
destabilize microtubules by inhibiting the assembly of tubulin heterodimers into microtubule
polymers or depolymerizing existing ones [10], [11]. And, according to the difference in binding site, microtubule-binding agents can
be divided into (1) agents binding to the colchicine-binding site; (2) agents binding
to the Vinca alkaloid-binding site; (3) agents binding to the taxane-binding site; or (4) agents
binding to other sites. The colchicine site is located at the interface between α and β subunits of the tubulin dimer, adjacent to the GTP-binding site of α-tubulin. The Vinca alkaloid-binding site is close to the exchangeable GTP
site on β-tubulin. The taxane-binding site is the NH2 terminal 31 amino acids of β-tubulin, a deep hydrophobic pocket.
Targets of microtubule-binding reagents in cancer therapy
The targets of microtubule-binding agents in cancer therapy include both cancer cells
and vascular endothelial cells. Microtubule-binding agents, either microtubule-stabilizing
agents or microtubule-destabilizing agents, could cause disruption of microtubule
dynamics and subsequent mitotic arrest and cell death in cancer cells. The mechanism
of their cytotoxic effects on tumor cells has been well studied [12], [13]. The clinical success of the presently available microtubule-binding agents in cancer
therapy was based mostly on their direct cytotoxic effects on tumor cells. Meanwhile,
recent studies have suggested that vascular endothelial cells could be another important
target of microtubule-binding agents in cancer therapy. Endothelial cells are highly
dependent on the tubulin cytoskeleton for their normal functions, including motility,
invasion, attachment, alignment and proliferation. Furthermore, compared with normal
endothelial cells, tumor-related endothelial cells are much more sensitive to the
activity of microtubule-binding agents [14]. Microtubule-binding agents
could exhibit both antiangiogenic and vascular-disrupting actions and their multiple
actions on endothelial cells cause a much greater reduction in the blood flow of tumors
than that of normal tissues [15]. Both preclinical and clinical studies have suggested that microtubule-binding agents
might be a particularly useful class of drugs for vascular-targeted therapy [16], [17].
Efforts have been made to isolate or rescreen microtubule-binding agents whose actions
more selectively target the tumor vasculature relative to their direct cytotoxic effects
on cancer cells. Combretastatins are the first microtubule-binding agents identified
to have tumor vascular disrupting activity at well-tolerated doses [18]. Combretastatin A-4 phosphate exhibits antiangiogenic activity both in vitro and in vivo
[19] and shows promising results in clinical trials [20]. Moreover, other vascular-targeted agents such as CA-1-P (Oxi4503), AVE8062, ABT-751,
TZT-1027, CYT997, Dolastatin 10, MPC-6827 (Azixa), NPI-2358, EPC2407, and MN-029,
have also progressed to clinical trials for cancer [21].
Drug resistance of microtubule-binding agents
Like other antimitotic agents, the usefulness of microtubule-binding agents is often
limited by the development of drug resistance. Drug resistance to microtubule-binding
agents could be mediated by multiple mechanisms. Among the causes of drug resistance,
multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters or
alteration of tubulin, the target of microtubule-binding agents, might be the most
important [22], [23], [24]. MDR is defined as the acquired resistance of cancer cells to many chemically diverse
anticancer drugs with different mechanisms of action [25]. The predominant cause of MDR is the overexpression and increase in drug transport
activity of ABC transporters. In addition, P-glycoprotein (P-gp), also known as ABCB1
or MDR1, is arguably the most important member of the ABC family [26]. The ABC transport systems contain two nucleotide-binding domains and two membrane
domains. ATP is bound and hydrolyzed at the nucleotide-binding domains and the vectorial
transport of substrates across
the cell membrane is mediated by the membrane domains. Recently, the crystal structures
of the bacterial P-gp homologues had been reported and the results shed light on the
possible conformational states adopted by ABC transporters during transport [27]. MDR mediated by ABC transporters might affect the efficacy of microtuble-binding
agents that could be recognized and transported by ABC transporters such as P-gp.
Besides ABC transporters, alterations in tubulin such as aberrant expression of class
III β-tubulin as well as changes in microtubule regulation were also associated with MDR
to microtubule-binding agents [22]. The key difference between class I and class III β-tubulin is an amino acid substitution (Arg277 in class III β-tubulin instead of Ser277 in class I β-tubulin) leading to a different three-dimensional conformation. The changed structure
of class III β-tubulin might prevent stable binding of microtubule-binding agents such as taxanes.
Furthermore, expression of class III β-tubulin might also generate more dynamic microtubules and counteract the
preassembling activity of taxanes at the plus ends of microtubules [28]. A recent study showed that the aberrant expression of class III β-tubulin caused drug resistance of microtubule-binding agents binding to taxane or
Vinca alkaloid binding sites but showed less effect on agents binding to the colchicine-binding
site [29].
Natural Products with Microtubule-Binding Activity
Natural products binding to the colchicine-binding site
Colchicinoids: Colchicine is a highly soluble alkaloid isolated from the meadow saffron, Colchicum autumnale. It is a well-studied tubulin-binding agent. In fact, in the past, tubulin was even
referred to as “colchicine binding protein”. Colchicine could cause microtubule depolymerization
by forming a stable complex with unpolymerized tubulin heterodimers. However, it would
cause severe toxicity at the doses required for exhibiting anticancer effects. Therefore,
colchicine is only used in therapy for gout but not for cancer. Recently, ZD6126,
a synthesized colchicine derivative, entered clinical trials as a vascular-targeting
drug [30]. It is a water-soluble phosphate pro-drug and would be converted in vivo into N-acetylcolchinol (ZD6126 phenol), which binds to the colchicine-binding site on tubulin.
ZD6126 affects endothelial cell morphology and disrupts newly formed vessels. In an
animal tumor model, it selectively induced tumor vascular damage and massive tumor
necrosis at well-tolerated doses [31]. Results of a phase 1 clinical trial of ZD6126 indicated that it was well
tolerated and the side effects included mild but manageable gastrointestinal adverse
events and dose-related cardiac toxicities [32].
Combretastatins: Combretastatin A-4 (CA4) was first isolated from the South African willow, Combretum caffrum in 1982. One of the advantages of CA4 is that it is not recognized by the ABC transporters
so CA4 does not induce MDR mediated by ABC transporters. Since CA4 has very limited
water solubility, water-soluble pro-drugs such as combretastatin A4 phosphate (CA4P)
have been synthesized. Several combretastatins, including CA4, CA4P and AC-7700 (AVE-8062),
are now in clinical studies. Like ZD2126, these reagents also target endothelial cells
and cause disruption of the endothelial cytoskeleton by acting at the colchicine-binding
site of the β-subunit of endothelial tubulin [33]. In addition to this, CA4P is also able to interfere with vascular endothelial-cadherin
signaling. By inducing regression of unstable emerging tumor neovessels, CA4P demonstrated
the ability to selectively target and disrupt tumor vasculature [34].
Natural products binding to the Vinca alkaloid-binding site
Vinca alkaloids:
Vinca alkaloids were originally isolated from the periwinkle plant Catharanthus roseus, also known as Vinca rosea. Vinca alkaloids are dimeric asymmetrical compounds with two multi-ringed subunits, vindoline
and catharantine, linked by a carbon–carbon bridge. Vincristine (Oncovin), vinblastine
(Velban) and vindesine are the first generation of Vinca alkaloids with antitumor activity. Vinblastine and vincristine were approved for
clinical use in 1961 and 1963, respectively. The success of natural vincristine and
vinblastine has led to the development of semisynthetic agents, including vindestine,
vinorelbine and vinflunine. Vinca alkaloids have a well-established role in treating a variety of malignancies including
hematological and lymphatic neoplasms as well as solid tumors such as breast cancer,
testicular cancer, choriocarcinoma and non-small cell lung cancer. However, the use
of Vinca alkaloids is restricted by drug resistance mediated by P-gp and side effects including
myelosuppression and neurotoxicity [35], [36], [37].
Vinflunine (Javlor) is now still in a phase III clinical trial. It is the first fluorinated
agent in the Vinca alkaloids family and is obtained by semisynthesis using superacid chemistry to selectively
introduce two fluorine atoms at the 20 position of the catharanthine moiety. Interestingly,
its non-fluorinated counterpart shows no similar antitumor activity which suggests
the essential contribution of the fluorine atoms to the antitumor activity. Similar
to other Vinca alkaloids, vinflunine suppresses microtubule dynamics by interacting with the Vinca alkaloid binding site on tubulin. However, compared with other Vinca alkaloids, vinflunine has the weakest affinity for tubulin and the binding of vinflunine
to tubulin is more readily reversible. These differences might lead to specific effects
of vinflunine on cell killing and the relatively low toxicity of vinflunine. Vinflunine
also induces drug resistance mediated by P-gp but the potency of vinflunine to induce
drug resistance is far weaker than that of vinorelbine. And, vinflunine is effective
on human tumor cell lines with an atypical (non-Pgp dependent) multidrug-resistant
phenotype. Besides, vinflunine has vascular-disrupting and antiangiogenic activities
both in vitro and in vivo
[38], [39]. In clinical trials, the main side effects induced by vinflunine, myelosuppression
and constipation, are apparently more manageable compared to those of other Vinca alkaloids [40]. In all, compared with vinorelbine, vinflunine shows better functions in efficacy,
tolerability and range of activity [41], [42], [43].
Hemiasterlins: Hemiasterlins are a family of natural peptides previously isolated from marine sponges
(Cymbastela sp., Hemiasterella minor, Siphonochalina sp., and Auletta sp.). They are tripeptides composed of three sterically congested amino acids that
are responsible for their activities. The three unusual amino acids in hemiasterlin
A are trimethyltryptophan, tert-leucine and N-methylhomo-vinylogous valine. By binding to the Vinca alkaloid-binding site of tubulin, hemiasterlins are highly potent in the suppression
of microtubule depolymerization [44], [45]. The total synthesis of hemiasterlins and analogues has been accomplished. The synthesis
of hemiasterlin was first reported in 1997 and a potent derivative taltobulin (HTI-286,
SPA-110), wherein a phenyl group replaces the 3-substituted indole ring, was synthesized
in 2003 [46]. HTI-286 showed potent in vivo cytotoxicity and antimitotic activity comparable to those of vincristine and paclitaxel
and also had the advantage of circumventing drug resistance mediated by
P-gp [47]. Extensive structure–activity relationship studies of HTI-286 analogues had been
conducted and other superior analogues such as HTI-042 were discovered [48]. Both HTI-286 and hemiasterlin are now in clinical trials.
Natural products binding to the taxane-binding site
Taxanes: Taxanes, specifically paclitaxel (Taxol), was initially extracted from the bark of
the Pacific Yew, Taxus brevifolia. The anticancer activity of paclitaxel was found during a National Cancer Institute
screen of plant extracts in the 1970s. The sample used was an extract collected by
the U. S. Department of Agriculture in 1962 [49]. Paclitaxel was approved for clinical use in 1992. Now, paclitaxel is obtained by
a semisynthetic method from 10-deacetylbaccatin III, which is extracted from the needles
of the European yew tree, Taxus baccata. Docetaxel (Taxotere), a semi-synthetic taxane approved for clinical use in 1996,
was also synthesized from 10-deacetylbaccatin III. Paclitaxel and docetaxel are both
hydrophobic compounds with a taxane ring core, esterification at the C-13 position
with a complex ester group, and an unusual fourth ring at the C-4,5 position. Paclitaxel
and docetaxel both have the tricyclic taxane skeleton while the distinction between
them is the different substituents at C-10 and on the C-13 side chain [50]. By binding to β-tubulin, taxanes promote
the polymerization of tubulin, stabilize microtubules, and perturb microtubule dynamics,
which eventually leads to apoptosis. The binding mechanism of taxanes with microtubules
has been well studied. They bind to polymerized microtubules within the lumen of the
polymer and stabilize GDP-bound β-tubulin protofilaments by straightening them into a conformation resembling the more
stable GTP-bound structure [51], [52], [53]. Since docetaxel has a higher affinity for the taxane-binding site than paclitaxel,
its effects on cancer cells are also different from that of paclitaxel. For example,
paclitaxel induces cell cycle arrest at the G2-M phase while docetaxel exerts its
maximum cell-killing effect on cells in the S phase. Peripheral neuropathy, one of
the side effects of taxanes, appeared less frequently and less severely under docetaxel
treatment than under paclitaxel treatment [54]. At present, both paclitaxel and docetaxel are widely used in the treatment of solid
tumors including breast cancer, ovarian cancer and lung cancer.
The clinical use of the taxanes is limited mainly by drug resistance and toxicity.
The resistance to taxanes is multifactorial and might involve the overexpression of
the membrane efflux pump P-gp, tubulin mutations and increased microtubule dynamics
associated with altered microtubule-associated protein (MAP) expression [55]. Taxane treatment has been shown to induce P-gp expression, leading to acquired
drug resistance. Efforts have been continually conducted to find Pgp inhibitors for
combination therapy with taxanes [56], [57]. And, another important cause of taxane resistance is the unnormal expression of
the class III isotype of β-tubulin [58], [59]. The toxic effects of taxanes include neutropenia, mucositis, neuropathy and hypersensitivity
reactions. The hypersensitivity reactions are mainly caused by formulations used to
improve the solubility of these drugs. Due to the poor solubility of these drugs,
they have to be administered in formulations including surfactants such as polyoxyethylated
castor oil
(Cremophor) or polysorbate.
New members of the taxanes family with higher activity and lower toxicity are being
continuously developed. Derivatives of paclitaxel overcoming transport-based resistance
for taxanes have been designed and synthesized. XRP9881 (Larotaxel) and TPI287 are
semisynthetic paclitaxel derivatives that circumvent the taxane resistance mediated
by P-gp because they are poor substrates for P-gp. XRP9881 (Larotaxel) and TPI287
are now both in phase II clinical trials [4].
To ameliorate the toxicity caused by a vehicle, new formulations of taxanes are being
developed and several of them are currently progressing through the clinic [60]. New formulations such as albumin, nanoparticles, emulsions, liposomes, and polyglutamates
are being developed to handle the poorly soluble taxanes. For example, ABI-007 (Abraxane)
is a novel albumin-stabilized, nanoparticle (mean particle size of about 130 nm) form
of paclitaxel for injectable suspension. It shows superior efficacy and less toxicity
than Cremophor-containing paclitaxel. The increased solubility of ABI-007 could strongly
decrease the time required for drug administration, from 3 h to 30 min [61], [62]. ABI-007 was approved by the FDA in January 2007 for the treatment of metastatic
breast cancer and is still undergoing further clinical trials against other solid
tumors. ANG1005 (Angiochem) is another modified formulation of paclitaxel. Containing
paclitaxel molecules conjugated to a receptor-targeting peptide, ANG1005 is selectively
transported across the blood-brain barrier and as such shows
efficacy against intracerebral tumors in mice [63]. ANG1005 is now in early stage clinical trials.
Epothilones: Epothilones belong to a new family of non-taxane microtubule-stabilizing agents.
Naturally occurring macrolides, such as epothilone A and epothilone B, were isolated
as secondary metabolites from the myxobacterium Sorangium cellulosum in the early 1990s [64]. The common structure of the epothilones is a 16-membered ring macrolide that is
covalently attached to a methylthiazole side chain. Based on the presence of or absence
of an epoxide group in the C-12 to C-13 position of the macrolide ring, naturally
occurring epothilones can be classified as epoxides (epothilones A, B, E, and F) or
olefins (epothilones C and D). The myxobacterial origin of epothilones makes them
relatively easy to be cultured and isolated on a large scale [65].
Ixabepilone (aza-epothilone B, BMS-247550), the newest epothilone approved for clinical
use in 2007, was semisynthesized from epothilone B by the substitution of an azide
group for oxygen at position 16 of the macrolide ring. Several members of the epothilone
family, including patupilone (EPO 906, a natural epothilone B), KOS-862 (epothilone
D), BMS-310705 (a second-generation epothilone B), ZK-EPO (a third-generation epothilone
B) and KOS-1584 (a second-generation epothilone D) are under clinical trials [66]. Since epothilones compete with paclitaxel in tubulin-binding, it is proposed that
they might target at or near the same binding site of taxanes on β-tubulin. Therefore, these two compound families have almost identical targets and
mechanisms of action. The marked difference in chemical structure supports the difference
in function between epothilones and taxanes. The most important difference is that
epothilones can overcome drug resistance mediated by P-gp. Therefore, compared with
taxanes, epothilones exhibit improved pharmacological and resistance profiles both
in vitro and in vivo
[67], [68], [69].
Natural products binding to other sites on tubulin
Natural products with binding sites not belonging to the three well-known tubulin-binding
sites (colchicine-binding site, Vinca alkaloid-binding site and taxane-binding site) have been found. Among them, laulimades,
pelorusides, taccalonolides and halichondrins could serve as good examples.
Laulimalides: Laulimalides, also known as fijianolides, are a family of polyketide natural products
of marine origin. They can be isolated from several species of marine sponges. Laulimalide
(fijianolide B) and its isomer isolaulimalide (fijianolide A) were isolated almost
contemporaneously by two groups from the marine sponges Cacospongia mycofijiensis, respectively Hyatella sp. and a nudibranch predator Chromodoris lochi in 1988. From the sponge Fasciospongia rimosa, a third isomer named neolaulimalide as well as laulimalide and isolaulimalide were
isolated in 1996. Further studies led to the isolation of six additional fijianolides
(D – I) from Cacospongia mycofijiensis
[70].
Laulimalides are microtubule stabilizers. Like taxanes, laulimalide could block normal
mitotic spindle formation and cause condensation of disorganized chromosomal material
in the center of cells. The fact that they can show synergism with taxanes indicates
that they have a non-taxane binding site on tubulin [71]. Besides, laulimalides show antiangiogenic activities and they are effective on
P-gp overexpressing cell lines [72], [73]. However, the clinical usefulness of laulimalides might be limited by their high
toxicity. A number of laulimalide derivatives are continuing to be synthesized and
subjected to pharmacological evaluation. Compounds with retained efficacy but with
decreased toxicity might hopefully be found in the future [74], [75], [76].
Pelorusides: Peloruside A is a polyoxygenated 16-membered macrolide of marine origin. In 2000,
it was isolated as a secondary metabolite from the New Zealand marine sponge Mycale hentscheli
[77]. Its 16-membered macrolide ring is similar to that of the epothilones. Peloruside
A shows toxicity at nanomolar concentrations and it works in a manner similar to paclitaxel
by stabilizing the polymerized form of microtubules. Like laulimalide, peloruside
A also has a non-taxane binding site and showed synergism with taxanes [78], [79], [80]. Recent studies indicate that peloruside A might bind within a pocket on the exterior
of β-tubulin at a previously unknown ligand site, rather than on α-tubulin as suggested in earlier studies. The effects of peloruside A arise from interactions
with the α/β-tubulin intradimer interface as well as protofilament contacts [81]. A number of synthetic studies about peloruside A have already been reported [82]. Peloruside B, possessing the 3-de-O-methyl variant of peloruside A, was just recently isolated from the New Zealand marine
sponge Mycale hentscheli. The bioactivity of peloruside B was comparable to that of
peloruside A in promoting microtubule polymerization and arresting cells in the G2/M
phase of mitosis [83].
Taccalonolides: Taccalonolides are a new class of plant-derived natural steroids with microtubule-stabilizing
activity. They are the first plant-derived microtubule-stabilizing agents to be identified
since paclitaxel and the first natural steroids to exhibit this activity. Taccalonolide
A was first isolated from the tropical plant Tacca plantaginea in 1987 and taccalonolide E was isolated in 1991. Similar to other microtubule stabilizers,
taccalonoids induce the formation of abnormal mitotic spindles leading to mitotic
arrest, Bcl-2 phosphorylation, and initiation of apoptosis [84]. However, results of in vitro studies showed that taccalonoids fail to modulate tubulin assembly or to bind microtubules.
These results suggested a distinct mechanism of taccalonoids compared with all other
microtubule-targeting agents [85]. Recent studies showed that the advantages of taccalonoids might include efficacy
in cell lines and tumors with taxane-resistance mediated by Pgp or class III β-tubulin. Therefore, with a distinct structure and mechanism, taccalonolides have
advantages over the
taxanes in their ability to circumvent multiple drug resistance mechanisms [86], [87].
Halichondrins: Halichondrins are large polyether macrolides first from the western Pacific sponge
Halichondria okadai and subsequently from several unrelated sponges belonging to the Axinella family. All of the members of the halichondrin family possess an unusual 2,6,9-trioxatricyclo[3.3.2.0]decane
ring system, as well as a 22-membered macrolactone ring, two exocyclic olefins, and
an array of polyoxygenated pyran and furan rings that define three major classes of
halichondrins, i.e., halichondrin A, B, and C [88]. The total syntheses of halichondrin B and norhalichondrin B as well as analogues
such as E7389 have been accomplished. E7389 (eribulin mesylate) is currently in phase
III clinical trials for the treatment of metastatic breast cancer. Phase I and phase
II clinical trials have demonstrated that eribulin was active in heavily pretreated
individuals while maintaining a tolerable therapeutic index. Its most frequent adverse
effects were neutropenia and fatigue. Since halichondrins exhibit activity as a noncompetitive
inhibitor of vinblastine binding to tubulin and has no effect on colchicine binding,
halichondrins were considered to bind tubulin at or near the Vinca alkaloid-binding site. Eribulin treatment resulted in a decrease in dynamicity by
suppressing the growth parameters at microtubule plus ends without affecting microtubule
shortening parameters [89]. Interestingly, recent studies suggested that eribulin might bind tubulin and microtubules
through a novel action. Eribulin was shown to bind to a single site on soluble tubulin
with a low affinity and to a very small number of sites at microtubule ends with a
high affinity. And, binding of vinblastine to microtubules inhibited eribulin binding
at low eribulin concentrations but also appeared to open additional, low-affinity
binding locations for eribulin, at either one or both microtubule ends [90].
