Interdisciplinary Neurosurgery: Advanced Techniques and Case Management 1 (2014) 1115

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Interdisciplinary Neurosurgery:
Advanced Techniques and Case Management
journal homepage: www.inat-journal.com

A hypothesis about the potential role of statin administration as

adjuvant treatment in the management of Merlin-decient tumors
Alexandros G. Brotis, MD, PhD a,, Parmenion P. Tsitsopoulos, MD, PhD b,
Tsiamalou M. Paraskevi, RN, PhD c, Anastasia Tasiou, MD, PhD c, Concienzio Di Rocco, MD, PhD d,
Kostas N. Fountas, MD, PhD c
a
Hygeia Hospital Tirana, Albania
b
Hippokration General Hospital, Thessaloniki, Greece
c
University Hospital of Larissa, Biopolis, Larissa, Greece
d
Polykliniko A. Gemeli, Largo A. Gemelli, Rome, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Merlin, a tumor suppressor protein, controls essential steps of cell cycle, and its deciency results in
Received 5 December 2013 cellular overgrowth, proliferation, angiogenesis, invasion and metastasis. Lack of Merlin is responsible
Revised 4 February 2014 for neurobromatosis-2, most schwannomas, and many meningiomas and ependymomas. We
Accepted 17 February 2014
hypothesize that there is a role for statins to ameliorate Merlin's deciency in this set of tumors by
inhibiting a number of Merlin's downstream effectors, the small Rho-GTP-ases, and we present the
Keywords:
Merlin-decient tumors
relevant data. The ultimate goal is to offer a medical therapy promising to halt or reduce the tumor
Rho-GTP-ases growth-rate in patients harboring Merlin-decient neoplasms and to provide an adjuvant systemic
Statins therapy for patients undergoing stereotactic radio-surgery and partial tumor resection.
2014 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license.

Introduction associated with neurobromatosis-2 (NF-2) [911]. Today, germ-

Meningiomas and schwannomas are benign central nervous
system tumors, and constitute 40% and 10% of all primary
intracranial tumors, respectively [1]. Moreover, ependymomas,
which are malignant primary CNS tumors, represent 10% of the
posterior fossa tumors in children [2]. All these types of CNS tumors
have been associated with neurobromatosis type-2 (NF-2), a
familial multiple neoplasia syndrome. It is inherited in an
autosomal dominant manner, and demonstrates 100% penetrance
by the 60th year of age [3,4]. Its incidence has been reported to be as
high as 1/25000 live births [5]. Its cranial manifestations include
bilateral vestibular schwannomas, and multiple and aggressive
meningiomas and ependymomas [5,6]. It has been demonstrated
that Merlin-decient tumors are frequent and can be multiple in
certain patients [1,7]. The tumor suppressor Merlin is a regulatory
mediator of the cell cycle [810]. Its deciency has initially been
No funds in the form of grants have been received in any process related to the
present manuscript.
Corresponding author at: Hygeia Hospital, Tirana, Albania, KM 01 Rruges
Dytesore te Autostades Tirane Durres, Tirana, Albania. +355696039085 (Mobile);
fax: +35542390000.
E-mail address: alexgbrodis@yahoo.com (A.G. Brotis).
line mutations of the NF-2 gene have been described in 4566% of
sporadic schwannomas [12,13], 60% of sporadic meningiomas, and
33% of sporadic ependymomas [13]. Embryos with homozygous
mutations of the NF-2 gene die in utero [14].
Multiple treatment modalities have been employed in the
management of the above mentioned neoplastic entities, either in
their NF-2 associated or in their sporadic forms. These include
extensive, surgical resection, conventional radiotherapy and ste-
reotactic radio-surgery [6,15,16]. All these disciplines carry inher-
ent high morbidity and considerable mortality risk [6]. New onset
damage to the facial and vestibulocochlear nerve are among the
most common postoperative complications in vestibular schwan-
noma surgery, with a reported frequency to be as high as 38% and
87%, respectively [17]. Moreover, the local nature of surgery and
stereotactic radio-surgery limits their usefulness in patients with
multimodal NF-2 [1]. Therefore, the development of new treatment
strategies is critical for managing these patients, and improving
their survival and their quality of life.
There is a growing body of evidence in the literature that the
absence of Merlin can be ameliorated by the administration of
statins, a group of drugs commonly employed in the prevention and
treatment of primary and secondary ischemic heart disease.
However, there is no literature-evidence, to the best of our

http://dx.doi.org/10.1016/j.inat.2014.02.003
2214-7519 2014 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license.
12 A.G. Brotis et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management 1 (2014) 1115
knowledge, supporting the use of statins in Merlin-decient
tumors. In our current communication, we hypothesize that statins
can be used in the prevention and management of these tumors,
and we provide the relevant evidence supporting this theory.
Merlin and tumor suppression
The NF-2 gene, identied in 1993, is a tumor suppressor gene
located on chromosome 22q12 and encodes a 69 kDa protein [8
11]. Its gene product, known as Merlin (Moesin-Erzin-Radixin-like
protein) or schwannomin [15,16,18], belongs to a greater protein
super-family, the Band 4.1 protein family, which includes band- 4.1-
erythrocyte protein, ezrin, radixin, and moezin proteins. These
proteins usually link the actin cytoskeleton to the cell surface
glycoproteins, to control cell growth, remodelling, motility and
invasion [15,16,18]. It exists in ten isoforms, with isoform-1 and 2
being the most common. All isoforms possess an N-terminal part,
which contains the four point one Erzin-Radixin-Moezin (FERM)
domain, followed by an alpha-helical domain, and a hydrophilic
tail [18].
Merlin is involved in the control of various aspects of the cell cycle
and the tumorigenesis (Fig. 1) [4,19,20]. It suppresses aberrant cell-
growth and proliferation by promoting the endocytosis of growth-
factor membrane receptors [19,21] and by controlling the transcrip-
tion/translation of Cyclin-D, a key cell-regulator of G1 phase and cell
cycle [19,2123]. It also demonstrates a pro-apoptotic effect of the
Fig. 1. Merlin has been considered a key regulator of various cellular pathways involved in (a) cell motility and proliferation (modied from Roy et al. [30]), (b) growth
(modied from Xiao et al. [4] and Scoles et al. [20]), (c) apoptosis (modied from Scoles et al [20]), (d) contact inhibition and (e) angiogenesis (modied from Wong et al [30]).
Dotted line = inhibition. Continuous line = promotion.
senescent cell by inhibiting the Ra-1 guanidine nucleotide dissocia-
tion stimulators (Ra-1 DGs) [20]. Moreover, Merlin has a protective
role against tumor invasion and metastasis through contact inhibi-
tion at the tight and adherent junctions, and also by regulating actin
cytoskeletal dynamics responsible for the formation of lamellopodia
[4,2429]. Furthermore, it has been demonstrated that Merlin
regulates angiogenesis in normal cells by means of semaphorin
3 F [30].
A common feature among all these pathways is the pivotal role
of proteins belonging to the Ras superfamily [31]. These are small
GTP binding proteins, which consist of ve subfamilies: Ras, Rho,
Rab, Ran and Arf [31]. The Ras family mediates extracellular signals
into the cell, and controls gene transcription, cell growth and
differentiation. In humans there are Ras oncogenes that regulate
cell proliferation, differentiation morphology, and apoptosis [31].
The Rho subfamily includes, among others, the RHO, RAC, and
CDC42 proteins, and is involved in cytoskeletal organization, cell
polarity, gene expression, and cell cycle progression [31]. The Rab
and Raf families are involved in endocytotic and secretory
functions, while the Ran family controls nuclear transport [31].
All members have been evolutionary preserved across several
phyla, and possess an N-terminal with GTP-ase properties and a
C-terminal [31].
The N-terminal switches from an active (GTP-bound) form to an
inactive (GDP-bound) [31]. The balance between these two forms is
mediated by two groups of regulatory molecules. The rst group,
 A.G. Brotis et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management 1 (2014) 1115
Fig. 2. Merlin oscillates between an active and an inactive state depending on
the phosphorylation of Rho-GTP-ases. Dotted line = inhibition. Continuous
line = promotion (modied from Xiao et al. [4]).
the guanine-nucleotide exchange factors (GEFs), activated by
various signals, promote the formation of the active form. The
second group, the GTP-ase activating proteins (GAPs) promote the
hydrolysis of the active to the inactive form [32]. Moreover, these
proteins require either geranylgeranylation or farnesylation or both
at their C-terminal before reaching their mature form, a process
which takes place during their post-translational modication. This
process is essential for proper intracellular localization and function
[33]. However geranyl-geranylation and farnesylation are part of
the HMG-CoA pathway, whose limiting step is enhanced by HMG-
CoA and is blocked by statins [34].
The interplay between the Rho-GTP-ases and Merlin becomes
even more interesting as Rac and Cdc-42 control the activation
status of Merlin (Fig. 2). The latter oscillates between an active and
an inactive form, by the phosphorylation on serine-518, a reaction
mediated by p-21 activated kinase (PAK) [24]. However, PAK is a
downstream product in the Rac and Cdc42 pathway [4].
Knock-down of both NF-2 gene alleles is required in Merlin-
deciency states according to the two-hit-hypothesis of Knudson
Fig. 3. Merlin is a tumour suppressor protein (a). Its deciency is predisposes for schwannomas, meningiomas and ependymomas due to uncontrolled action of the
Rho-GTP-ases (b). We hypothesize that inhibition of the prenylation of Rho-GTP-ases after the administration of statins would ameliorate Merlin's deciency (c). Empty
arrow = inhibition.
13
[35]. A pathologic gene allele might occur either de novo or be
inherited. Mutation of the second allele will result in a pathologic
cell-lineage, responsible for the patients phenotype in suscepti-
ble organ systems [15,16].
Our hypothesis
Our hypothesis is to use the statins in order to ameliorate the
absence of Merlin in Merlin-decient tumors (Fig. 3). Merlin
controls the cell cycle by inhibiting the small Rho-GTP-ases. In the
absence of Merlin, the latter act in an uncontrolled manner leading
to tumor development. Statins blockade of the melavonate
pathway would inhibit the biosynthesis of small Rho-GTP-ases,
Rho, Ras, Rac, and Cdc-42, parallel to the inhibition of cholesterol.
Inhibition of the small Rho-GTP-ases biosynthesis would down-
regulate both the external and internal growth signals, permit
contact inhibition, slow cellular proliferation, control angiogenesis,
invasion, and metastasis. In case of any remaining Merlin effect, the
statin administration would enhance its action by unmasking its
suppression by the small Rho-GTP-ases. In other words, statins
would take the lost control of the cell cycle instead of Merlin.
The aim of administering statins in patients with Merlin-
decient tumors is to halt or slow the progression of these
neoplasms, decreasing thus, the total number of surgery or
radiotherapy candidates. Statins can also be used as an adjuvant
therapy in cases with partial tumor resection or stereotactic radio-
surgery. Furthermore, NF-2 patients would receive a systemic
therapy, in addition to the regional treatments, that potentially
would improve their quality of life and increase their life
expectancy.
Statins
Statins are a group of substances which inhibit the enzyme
HMG-CoA reductase, and as a consequence are potent suppressors
of cholesterol biosynthesis [36]. They were developed in the 1980s
after noting that a fungal metabolite (mevastatin, compactin) could
14 A.G. Brotis et al. / Interdisciplinary Neurosurgery: Advanced Techniques and Case Management 1 (2014) 1115
inhibit a critical step in the melavonate pathway lowering thus, the
circulating levels of endogenous cholesterol [37,38]. Up-to-date,
nine statins have been studied extensively, eight of which are
currently used (lovastatin, mevastatin, simvastatin, atorvastatin,
pravastatin, uvastatin, rosuvastatin and pitavastatin) in clinical
practice, and one was withdrawn (cerivastatin) due to reported
side effects [39]. Their pharmacokinetic and pharmacodynamic
properties and their safety prole are important parameters in their
consideration in the management of Merlin-decient tumors.
Statins are orally administered, with considerable variations
regarding their dosage (10-80 mg/day), hydrophilic prole, tissue
availability, and metabolism. Among them, pravastatin and rosu-
vastatin are extremely hydrophilic, atorvastatin, simvastatin,
pitavastatin and lovastatin are hydrophobic, while uvastatin is
somewhere in the middle [40,41]. All statins exhibit signicant liver
rst-pass effect. The cytochrome 450 plays a pivotal role in most
hydrophobic statin metabolism, in contrast to the hydrophilic
statins and pitavastatin [4144]. Statins (with the exception of
pravastatin) are largely bound to serum proteins, and thus the
resulting systemic exposure to the unbound active substance is
minimal [41]. Simvastatin and lovastatin are the most potent drugs
in terms of crossing the blood brain barrier, achieving effective
concentrations in the cerebrospinal uid, with uvastatin and
pravastatin being on the other edge [4548].
Nowadays, statins are widely used in the primary and secondary
treatment of coronary artery disease, diabetes mellitus, ischemic
stroke, and renal dysfunction [49,50]. Their primary target-organ is
the liver, which mediates their action mainly by lowering the total
and LDL cholesterol. Their lipid lowering properties are manifested
in nanomolar serum concentrations and are achieved by their
structural similarity to HMG-CoA and their reversible competitive
binding to the HMG-CoA reductase [36,38]. In addition, there is
abundance of evidence indicating that statins benecial function is
largely cholesterol-independent [49]. These collateral benets are
known as the pleiotropic effects of statins and are manifested by
inhibition of the biosynthesis of isoprenoids [34]. The latter affect
the post-translational modications of intercellular signaling
molecules and can be classied as anti-inammatory, immuno-
modulatory or anti-neoplastic [36,49,51,52]. The pleiotropic effects
have been reported to occur at higher concentrations [52], and
provoke the expansion of the listed indications on the use of statins
in a number of other conditions including Alzheimer's disease,
Parkinson's disease, multiple sclerosis, subarachnoid hemorrhage,
traumatic brain injury, medulloblastomas, and pancreatic cancer.
The safety prole of statins is excellent, with myalgia being the
commonest reported adverse effect (7%), followed by myopathy
(b 0.2%), rhabdomyolysis (b0.05%), diabetes mellitus, and asymp-
tomatic transaminasaemia to a lesser extent [44,53]. Despite the fact
that most of these side effects are dose-dependent, statins are well
tolerated in higher doses [44]. In addition, statins present important
interactions with other drugs that share the same enzyme substrate,
such as antiretrovirals, calcium channel blockers, and gemfebrosil
[44,53].
From bench to bedside
Recent in vitro studies support our hypothesis. Lovastatin
inhibits the proliferation of meningioma cells in vitro in a dose
dependent manner, an effect that is partially reversed by the
administration of melavonate [54]. Meningioma cell-lines have
been reported to be sensitive to the cytotoxic effect of simvastatin,
which is moderately enhanced by the addition of pioglitazone [55].
However, before moving from theory to clinical praxis and
administer statins to patients with Merlin-decient tumors, a few
important parameters should be controlled. Are Merlin-decient
schwannomas and ependymomas inhibited by statins in vitro? Are
statins effective in Merlin decient tumors in vivo, as well? If yes,
which statin and in what dose should be preferred? It is reminded
that the pleiotropic effects are substance- and dose-dependent [55].
The chosen statin should cross the blood brain barrier and maintain
sufcient concentration in brain tissue and cerebrospinal uid, with
the least systemic toxicity, in order to achieve the desired results. It is
expected that the anti-neoplastic effect would be achieved with high-
dose statin regimen [56]. In addition, controlled studies comparing
the tumor progression in patients on statins with controls (or the
disease N natural history) would justify our hypothesis. Finally,
another set of studies would select the optimal target population in
terms of age, disease stage, and de-novo versus inherited cases.
A number of difculties are well anticipated in testing our
hypothesis. Many of the biochemical pathways that describe
Merlin's function are at an investigational level. Similarly, there is
still confusion regarding the pleiotropic effects of statins. On the
other hand, highly specialized laboratories are needed to culture
Merlin-decient schwannoma and meningioma cell lines and test
the cytotoxicity of statins. In addition, the in-vivo testing of our
hypothesis demands the participation of a large patient sample for
a long time, undergoing expensive investigations (magnetic
resonance imaging), repeatedly. Things are more difcult in the
case of NF-2 patients due to their rarity and lesion multiplicity. Only
special referral centers come across a sufcient number of NF-2
patients for a sufcient time in order to perform the above noted
studies. Finally, surgery is unavoidable for the present, since the
surgical access to the tumor cells is mandatory in order to verify
Merlin's deciency, downgrading statin's role to adjuvant therapy.
Concluding, there is a potential role of statins in the manage-
ment of Merlin-decient tumors based on their pleiotropic effects.
However, it is expected to be manifested by statins that cross the
blood brain barrier and in higher doses. The aim is to halt or slow
these tumors, especially in NF-2 patients. However, further studies
are needed to validate the present hypothesis.
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