HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

Abstract

The statin family of drugs target HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

Full text

Leukemia (2002) 16, 508–519
 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00
www.nature.com/leu
SPOTLIGHT
REVIEW
HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as
triggers of tumor-specific apoptosis
WW-L Wong
1,2
, J Dimitroulakos
1
, MD Minden
1,2
and LZ Penn
1,2
1
Department of Cellular and Molecular Biology, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto,
Canada; and
2
Department of Medical Biophysics, University of Toronto, Toronto, Canada
The statin family of drugs target HMG-CoA reductase, the rate-
limiting enzyme of the mevalonate pathway, and have been
used successfully in the treatment of hypercholesterolemia for
the past 15 years. Experimental evidence suggests this key bio-
chemical pathway holds an important role in the carcinogenic
process. Moreover, statin administration in vivo can provide an
oncoprotective effect. Indeed, in vitro studies have shown the
statins can trigger cells of certain tumor types, such as acute
myelogenous leukemia, to undergo apoptosis in a sensitive
and specific manner. Mechanistic studies show bcl-2
expression is down-regulated in transformed cells undergoing
apoptosis in response to statin exposure. In addition, the apop-
totic response is in part due to the depletion of the downstream
product geranylgeranyl pyrophosphate, but not farnesyl pyro-
phosphate or other products of the mevalonate pathway includ-
ing cholesterol. Clinically, preliminary phase I clinical trials
have shown the achievable plasma concentration corresponds
to the dose range that can trigger apoptosis of tumor types in
vitro. Moreover, little toxicity was evident in vivo even at high
concentrations. Clearly, additional clinical trials are warranted
to further assess the safety and efficacy of statins as novel
and immediately available anti-cancer agents. In this article, the
experimental evidence supporting a role for the statin family of
drugs to this new application will be reviewed.
Leukemia (2002) 16, 508–519. DOI: 10.1038/sj/leu/2402476
Keywords: HMG-CoA reductase; statins; apoptosis; geranylgeran-
ylation; bcl-2
Introduction
A new opportunity for the development of novel anti-cancer
therapeutic agents has recently been realized with the dis-
covery that cells are programmed with the potential to commit
suicide through the molecular mechanism of apoptosis (for
recent reviews see Refs 1–4). This apoptotic process is highly
regulated at the cellular level by a multiplicity of independent
and interdependent pathways.
5–11
Deregulation within the
apoptotic network contributes to tumor development by
allowing cells to evade signals to commit suicide,
12
yet para-
doxically, transformed cells often retain the ability to undergo
apoptosis. Proof of concept is provided by traditional chemo-
therapeutic agents that inhibit DNA synthesis or cellular repli-
cation, often leading to irreparable DNA breaks, cell cycle
arrest and ultimately apoptosis of the tumor cells.
13
However,
application of such agents is often limited by significant tox-
icity and a lack of specificity. Traditional cytotoxic agents
affect both normal as well as tumor cells, and can result in
toxic side-effects that significantly impact patient quality of
Correspondence: LZ Penn, Division of Cellular and Molecular
Biology, Ontario Cancer Institute, University Health Network, 610
University Ave, Rm 9–628, Toronto, Ontario, Canada M5G 2M9; Fax:
416-946-2840
Received 11 September 2001; accepted 21 January 2002
life.
13
Taken together, cancer eradication by chemotherapy is
achieved by triggering tumor cells to undergo apoptosis; how-
ever, the stimuli need to be radically modified to target tumor
cells in a more specific, less toxic manner (Figure 1). New
approaches through molecular targeted therapies promise to
fill this gap and provide the novel anti-cancer agents
urgently required.
A novel molecular target with strong potential for rapid
application to the clinic is the rate-limiting enzyme of the
mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase.
14
The end products of the mevalon-
ate (MVA) pathway are required for a number of essential
cellular functions (Figure 2). These include sterols, such as
cholesterol, involved in membrane integrity and steroid pro-
duction; ubiquinone (coenzyme Q), involved in electron
transport and cell respiration; farnesyl and geranylgeranyl iso-
prenoids involved in covalent binding of proteins such as the
Ras family to membranes; dolichol, which is required for gly-
coprotein synthesis; and isopentenyladenine, essential for cer-
tain tRNA function and protein synthesis.
14–18
Importantly,
inhibitors of this key enzyme, collectively known as statins,
are well established and effective agents used in the treatment
of hypercholesterolemia.
19–22
Thus, HMG-CoA reductase is a
unique molecular target for anti-cancer therapy; it holds a piv-
otal role in the well-defined MVA pathway, and a specific
family of inhibitors is available for immediate application in
the cancer clinic.
Recent evidence strongly suggests the MVA pathway holds
an important regulatory role in cellular proliferation and trans-
formation. For example, malignant cells appear highly depen-
dent on the sustained availability of the end products of the
MVA pathway.
23–25
Deregulated or elevated activity of HMG-
CoA reductase has been shown in a range of different tumors
Figure 1 Novel chemotherapeutic agents are required that induce
apoptosis of malignant cells in a sensitive and specific manner.

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
509
SPOTLIGHT
Figure 2 The mevalonate pathway.
including hepatocellular carcinoma, leukemia, lymphoma,
colorectal and lung adenocarcinoma.
26–31
Moreover, large
retrospective analyses for drug safety and efficacy trials of stat-
ins in coronary artery disease have shown, that not only are
these agents able to reduce cardiac disease-related mortality,
but cancer incidence is also reduced by 28–33%.
32,33
These
data further suggest these agents may have a role in cancer
prophylaxis as well as therapy.
19,32–35
Indeed, recent analyses
have demonstrated that inhibitors of HMG-CoA reductase can
directly block tumor cell growth both in vitro and in vivo.In
this review, we will focus on the antiproliferative activity of
the statins, the mechanism of statin-induced apoptosis, and
the application of statin therapy as an anti-cancer agent.
The statin family of drugs
The statin family is composed of eight unique compounds that
are naturally derived or chemically synthesized (Figure
3).
22,36–39
Statins derived from fungal fermentation include
pravastatin, simvastatin, and lovastatin, whereas fluvastatin,
atorvastatin, cerivastatin, rosuvastatin and pitavastatin
NK-104
are synthetic compounds.
40–47
The common structural charac-
teristic of all statins is a side chain that exists either in a closed
ring (inactive, lactone) or an open ring (active, acid) form
(Figure 2).
48,49
The former undergoes activation in vivo by car-
boxyesterases in plasma and liver.
50,51
The open ring confor-
mation of this drug blocks catalytically active HMG-CoA
reductase by functioning as a molecular mimic of a reaction
intermediate formed within the active site of this enzyme.
49
Statins are effective competitive inhibitors as they bind HMG-
CoA reductase approximately1000-fold more effectively than
the natural substrate.
36,49
Each member of the statin family of drugs functions by a
similar mechanism of action but maintains unique binding
affinities, pharmacokinetics and dosing levels (Table 1). A
detailed overview of these features is beyond the scope of this
article, and the reader is referred to several reviews of this
subject.
36,39,40,46,47,52–55
In brief, the binding affinities of the
Leukemia
inhibitors (K
i
) range from 0.1 to 2.3 nM,
36,45–47
whereas the K
m
of the natural substrate, HMG-CoA is 4
␮
M.
56
The pharmaco-
kinetics are disparate and largely dictated by their lipophilic
nature, acid or lactone form, and mechanism of cytochrome
P450 metabolism in the liver, which is the primary site of
action for cholesterol control.
57,58
Briefly, statin action for
hypercholesterolemia leads to a decrease in intracellular hep-
atic cholesterol levels which then induces expression of cell
surface low-density lipoprotein receptors, enabling choles-
terol to be removed from the circulation and replenish intra-
cellular cholesterol stores.
59
The safety of this family of drugs
has been documented extensively and they are remarkably
well tolerated.
21,22,39,55
Reports of minor adverse side-effects
include constipation, flatulence, dyspepsia, nausea, gastro-
intestinal pain, and elevated serum transaminase levels.
22,59
The most serious adverse effect is myotoxicity including rhab-
domyolysis which can be diminished with co-administration
of ubiquinone.
55,59
Patients with hepatic insufficiency, chol-
estasis, or hepatic or renal diseases warrant careful monitoring
when treated with statins.
57,59
In addition, drug:drug interac-
tions must be thoroughly considered to ensure systemic con-
centrations are controlled. This is of particular importance
with agents that are also metabolized by cytochrome P450
3A4 such as gemfibrozil.
33,37,55,60–66
Thus, the statins are func-
tionally equivalent and the choice of drug is largely deter-
mined by individual patient needs and tolerability.
Antiproliferative activities of statins
Growth arrest
It is well established that exposure of certain transformed cells
to statins in vitro can lead to growth arrest at the G1/S phase
boundary of the cell cycle.
67,68
Indeed, lovastatin is used rou-
tinely as an experimental tool to block G1 to S phase tran-
sition and to synchronize cells in vitro, by reversing the block
with the addition of mevalonate.
67
This characteristic has been
primarily exploited and studied in cell lines derived from

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
510
SPOTLIGHT
Leukemia
Figure 3 The statin family of drugs block the conversion of HMG-CoA to mevalonate by inhibiting the rate-limiting enzyme of the mevalonate
pathway, HMG-CoA reductase (a). The structural formulae of the statin family are shown in their open ring (active) form (b).

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
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SPOTLIGHT
Table 1 Characteristics of statins
Statin Characteristic
Lipophilic Form Source K
1
for IC
50
for Major Dosage for cholesterol (mg/day)
HMG-CoA HMG-CoA metabolism
reductase reductase by P450
(
nM
)
activity
(
nM
)
a
Lovastatin Yes
55
Lactone
57
Fungi
57
0.6
36
20
40
3A4
39
20–80
165
Simvastatin Yes
55
Lactone
57
Fungi
57
0.12
36
18.1
46
3A4
39
10–80
166
Pravastatin No
55
Acid
57
Fungi
57
2.3
36
55.1
46
Minimal
39
10–40
167
Fluvastatin Yes
55
Acid
57
Synthetic
57
0.3
36
17.9
46
2C9, 2D6
39
20–80
168
Atorvastatin Yes
55
Acid
57
Synthetic
57
NA 15.2
46
3A4
39
10–80
169
Cerivastatin Yes
55
Acid
57
Synthetic
57
1.3
45
13.1
46
3A4, 2C8
39
0.2–0.4
170
Rosuvastatin No
46
Acid
46
Synthetic
46
0.1
46
11.8
46
2C9, 2C19
37
5–80
37
Pitavastatin Yes
47
Acid
47
Synthetic
47
1.7
47
6.8
47
2C9, 2C18
47
4
47
a
In rat liver microsomes.
NA, not available.
mammary carcinomas but is also evident in other cell
types.
67,69–72
At the molecular level, this p53-independent
growth arrest response, is mediated by a down-regulation of
cyclin dependent kinase (CDK) 2 activity with an associated
up-regulation of CDK inhibitors p21
Cip1
and/or p27
Kip1
.
69,71–73
It has been recently suggested that this cytostatic activity can
be mediated by the closed ring, pro-form of lovastatin or sim-
vastatin by affecting proteasome function.
74,75
The precise
inhibitory mechanism of statins on the proteasome function
requires further clarification. Interestingly, these effects are
reversible with mevalonate
74–76
and a role for the pro-form of
lovastatin is not consistent with other results in the field. For
example, cerivastatin, an active open ring statin, can induce
the classical G1/S phase growth arrest with an associated
increase in p21
Cip1
in malignant breast cells.
77
Moreover, we
and others, have shown that the lactone ring is hydrolyzed to
its active form when exposed to aqueous solution, including
cell growth medium, strongly suggesting the pro-drug was
activated in these in vitro studies.
60,78,79
Taken together, statins
can growth arrest certain tumor sub-types by activating a well
defined cell cycle checkpoint at the G1/S phase border by a
mechanism that remains ill defined, but involves inhibition of
HMG-CoA reductase.
Apoptosis
In recent years it has become clear that inhibitors of HMG-
CoA reductase can trigger a subset of tumor-derived cells to
Table 2 Preliminary indications of tumor sensitivity to statin-
induced apoptosis in vitro
Tumor type Ref.
Acute myelogenous leukemia 80–82
Juvenile myelomonocytic leukemia 79
Squamous carcinoma of the head and neck 79
Squamous carcinoma of the cervix 79
Rhabdomyosarcoma 79
Medulloblastoma 79, 83
Mesothelioma 84
Astrocytoma 87
Pancreatic 85
Neuroblastoma 79, 86
Leukemia
undergo apoptosis (Table 2). Tumor cell types that undergo
apoptosis upon exposure to lovastatin include acute myelo-
genous leukemia (AML), juvenile monomyelocytic leukemia,
rhabdomyosarcoma, squamous cell carcinoma of the cervix
and of the head and neck; medulloblastoma, mesothelioma,
pancreatic carcinoma, neuroblastoma and astrocytoma.
79–87
Clearly, this list is not yet comprehensive. Further investi-
gation is essential to fully evaluate which additional tumor
types are sensitive to statin-induced apoptosis.
72,88–90
Sensitive
tumor types show a consistent pronounced apoptotic response
following statin exposure in vitro, suggesting these cancers
may have a high-probability of sensitivity in vivo. The molecu-
lar features conferring sensitivity to statin-induced apoptosis
remain unclear. Experimental evidence show cells must be
proliferating to be sensitive to statin-induced apoptosis.
91–94
However, being engaged in the cell cycle is essential but not
sufficient for statins to trigger an apoptotic response.
73,79,82
For
example, proliferating tumor-derived cell lines that are not
sensitive to statin-induced apoptosis in vitro include breast
and prostate.
79
Further work delineating the molecular fea-
tures conferring sensitivity to statin-induced apoptosis is a sub-
ject of intense investigation because of the therapeutic poten-
tial of statins to trigger tumor cells to undergo apoptosis in
vivo (discussed below). Statin-induced apoptosis occurs due
to the open-ring active drug blocking HMG-CoA
reductase.
79,95,96
Cell lines that have been rendered resistant
to lovastatin-induced apoptosis by exposure to increasing
doses of statins show drug-resistance is due to amplification
of the gene encoding HMG-CoA reductase.
97,98
In addition,
the apoptotic response is abrogated by the addition of excess
mevalonate to the sensitive cells.
88,99–104
Thus, cells of certain
malignant transformations are sensitive to statin-induced
apoptosis as a direct result of blocking HMG-CoA reductase
and the mevalonate pathway.
Most importantly, statins can trigger apoptosis in a tumor-
specific manner. The majority of both primary and established
tumor cells derived from AML undergo apoptosis in response
to lovastatin.
81,82,105,106
. By contrast, myeloid progenitor cells
derived from normal bone marrow or cord blood do not
undergo apoptosis and retain their full proliferative poten-
tial.
82,106
Further evidence that non-transformed cells of hema-
topoietic origin are not damaged by exposure to statins orig-
inates from animal studies as well as both low- and high-dose

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
512
SPOTLIGHT
Leukemia
human clinical trials (discussed below).
19,36,57,81,105–111
Thus,
despite the prevalence of HMG-CoA reductase in all cells,
data to date suggests statins will possess a high therapeutic
index (efficacy/toxicity) when used to target apoptosis-sensi-
tive tumor sub-types in vivo.
Molecular mechanism of statin-induced apoptosis
Understanding the mechanism of statin-induced apoptosis of
tumor cells is at its infancy and further investigation is
required to delineate the key features that dictate statin sensi-
tivity. One of the distinguishing molecular characteristics of
statin-sensitive AML and colon cells is the down-regulation of
bcl-2 mRNA and protein, respectively.
112,113
Although basal
bcl-2 mRNA levels are not associated with sensitivity to lovas-
tatin-induced apoptosis, down-regulation of bcl-2 is a consist-
ent feature of the lovastatin-sensitive AML cell lines.
112
Indeed, this molecular event contributes to the sensitivity of
the apoptotic response as ectopic expression of bcl-2 can
inhibit lovastatin-induced apoptosis.
112,114
The mechanism of
bcl-2 down-regulation following exposure to lovastatin is
unknown but is associated with a pronounced differentiation
response in AML cells. For example, elevated expression of
differentiation-specific cell surface antigens, CD11b and
CD18 was detected in response to lovastatin. Interestingly,
retinoic acid, a potent cell differentiating and growth inhibi-
tory agent, regulated bcl-2 as well as CD11b and CD18 in a
similar manner to lovastatin in the apoptosis-sensitive AML
cell lines.
112
The relationship between lovastatin-induced dif-
ferentiation and apoptosis are provocative and require further
investigation. Statin regulation of Bcl-2 expression and func-
tion is consistent with statin-induced apoptosis employing the
intrinsic mitochondrial pathway to effect cell death. Apoptosis
in response to lovastatin is associated with release of cyto-
chrome c, activation of caspase-3, and PARP cleavage in
AML.
115
The depletion of mevalonate is responsible for statin-
induced apoptosis in sensitive tumor cells, suggesting that
blocking the production of specific mevalonate metabolites
is involved in this process. To determine which downstream
product(s) of the mevalonate pathway could suppress this
apoptotic response, add-back experiments were conducted.
Of the many diverse downstream products of the mevalonate
pathway, only geranylgeranyl pyrophosphate (GGPP) was
able to inhibit apoptosis.
88,102,104
No effect was evident with
other products including cholesterol, ubiquinone, isopenteny-
ladenine and dolichol phosphate. Interestingly, farnesyl pyro-
phosphate (FPP), a molecule similar to GGPP, had little to no
effect on statin-triggered apoptosis in a variety of cell sys-
tems.
88,102,104
GGPP and FPP serve as substrates for geranyl-
geranyl transferases (GGTase) and farnesyl transferase (FTase),
respectively, which isoprenylate proteins to ensure proper
localization within the cell.
17
The importance of geranylgeran-
ylation in statin-induced apoptosis of AML cells was con-
firmed with inhibitors of geranylgeranyl transferase (GGTI-
298) and farnesyl transferase (FTI-277).
104
GGTI-298 was as
potent as lovastatin in triggering apoptosis, whereas FTI-277
showed little apoptotic activity.
104
Therefore, one possible
model is that exposure to statins depletes GGPP causing
improper localization and function of proteins which
ultimately triggers the cell to commit suicide (Figure 4).
It remains unclear whether global loss of protein geranylger-
anylation is key to apoptosis or whether loss of a restricted
substrate(s) is responsible for the apoptotic response to statin
Figure 4 One of many working models of the mechanism by
which statins trigger tumor-specific apoptosis. Exposure to statins
depletes the supply of geranylgeranyl pyrophosphate in the cell, lead-
ing to improper localization and function of geranylgeranylated pro-
teins which may disrupt a critical survival pathway and ultimately
induce apoptosis in the AML blast cell.
exposure. Approximately 0.5 to 1% of cellular proteins are
geranylgeranylated yet only a small number of substrates have
been identified.
116
Known target proteins include small GTP-
binding proteins including K-Ras and N-Ras as well as the Rho
family of proteins. Interestingly, statins have been shown to
block metastasis at the level of cell attachment, migration and
invasion in solid tumors.
77,117–122
Mechanistic studies strongly
suggest geranylgeranylation is also key to the anti-metastatic
properties of statins, and a pivotal role for RhoA in these
activities.
77,122
It will be fascinating to delineate whether simi-
lar or different target proteins are responsible for the pro-apop-
totic and antimetastatic properties of the statin family of drugs.
To this end, direct analysis of the geranylgeranylated proteins
in both apoptosis-sensitive and -resistant cells should begin to
address the issue of target specificity and apoptotic response.
Moreover, by this approach molecular markers to identify
tumor cells that will undergo apoptosis in response to statin
therapy may be achieved.
Analysis in three additional areas of research will further
identify distinguishing features of tumor cells that are sensitive
to statin-induced apoptosis. First, the nature and number of
transforming events that contribute to the statin-induced apop-
totic response remains relatively unknown.
123–125
Indeed, it
has become clear in recent years that certain transforming
events can significantly affect cellular apoptotic response. For
example, cytostatic agents block proliferation of non-transfor-
med cells, yet will trigger apoptosis in cells expressing an acti-
vated allele of the c-myc oncogene.
126
It will be instructive to
learn which specific transforming events contribute to statin
sensitivity. Secondly, cells of sensitive tumor types expressing
P-glycoprotein (P-gp) have been shown to be further sensi-
tized to the cytotoxic effects of lovastatin.
86,127–129
The mech-
anism of this remarkable characteristic has only recently been
explored and requires additional investigation.
62,63
Finally, an
important and often overlooked concept of apoptosis regu-
lation, is the cell type-dependent response. For example,
irradiation of T lymphocytes and fibroblasts leads to an induc-
tion of p53 expression that is similar at the molecular level in
both cell types, but only the lymphocytes undergo

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
513
SPOTLIGHT
apoptosis.
130
Cell type differences clearly contribute to the
multifunctional properties of statins. For example, statins can
function as anti-inflammatory agents, antioxidants, immunom-
odulators, and angiogenic agents depending on the non-trans-
formed cell type.
131–139
In addition, statins can block vascular
smooth muscle cell proliferation as well as signal endothelial
cell survival and progenitor cell expansion.
140–144
These
results underscore the cell type-dependent effects of statins
as well as the pleiotropic effects of these agents. Thus, the
parameters that confer sensitivity to certain tumor cells to
undergo statin-induced apoptosis require further investigation.
Complete mechanistic knowledge is key to optimal utiliz-
ation of statins in the clinical management of cancer in combi-
nation with other anti-neoplastic agents. For example, insulin
growth factor-1 (IGF-1) and nerve growth factor exposure of
mouse colon cancer cells and neuronal cells, respectively,
delayed the cytotoxic effects of lovastatin.
94,145
Similarly,
growth factors, estradiol and IGF-1 have been shown to
reverse the growth arrest phenotype triggered by lovastatin in
breast and melanoma cells, respectively.
146–148
These data
suggest that growth and survival pathways triggered by these
factors can overcome the anti-cancer effects of statins. Ident-
ifying the modulators of statin activity within these signaling
pathways may shed light on the mechanism of statin-directed
cytotoxicity. This knowledge may provide an opportunity to
further potentiate statin efficacy by combining inhibitors of
these modulators with statin therapy in vivo.
Preclinical evaluation of statins as anti-cancer agents
Analyses of cell culture and animal models of carcinogenesis
have shown that statins can decrease tumor cell number alone
and in combination with other anti-cancer agents. When
administered as the sole agent in animal models statins can
decrease tumor load of AML, melanoma, hepatoma, pancre-
atic, lung and neuroblastoma.
107,117,149–152
Importantly, there
was little overt toxicity. However, it is unlikely that an agent
will be effective in eradicating disease when administered by
itself, hence multiagent cancer therapy is practised. In parti-
cular, lovastatin has been shown to potentiate antitumor
activity of doxorubicin, TNF-
␣
, carmustine (BCNU; N, N⬘-
bis(2-chloroethyl)-N-nitrosourea) in mouse tumor models of
lung, colon carcinoma, melanoma and astrocytoma, respect-
ively.
153–157
Other statins, including lovastatin have been
shown to potentiate apoptotic effects of cytosine arabinoside,
phenylacetate, cisplatin, 5-fluorouracil, butyrate and non-ster-
oidal anti-inflammatory drugs (NSAIDs) such as sulindac in
AML, glioblastoma, and colon cancer cells.
71,102,113,158–160
Identifying agents that synergize with statins will aid in their
proper application in the clinic and may also help elucidate
the mechanism of statin-induced apoptosis.
Clinical trials
Clinical trials investigating the possible value of the statins as
chemotherapeutic agents have been recently conducted and
suggest dosing and scheduling are important (Table 3). In the
first phase I clinical trial lovastatin was administered at a dose
of 25 mg/kg/day in four divided doses by the usual oral route
for 1 week followed by 3 weeks off statin administration.
Dose-related toxicities were minimal and consisted of gastro-
intestinal dysfunction, and musculoskeletal system complaints
including mylagias and muscle weakness.
109
Supplementation
Leukemia
with ubiquinone reduced the severity but did not decrease the
incidence of musculoskeletal toxicity or affect drug activity as
a cholesterol agent.
109
Interestingly, at doses higher than 25
mg/kg/day, no direct correlation between the incidence of
myotoxicity and the dose of lovastatin administered was evi-
dent.
109
Most importantly, the trial established the achievable
plasma concentration at 0.10 to 3.92
␮
M at a dose of 25
mg/kg/day, which corresponds to the dose range that can trig-
ger apoptosis of sensitive tumor types in vitro.
79,82
Interpatient
variability in achievable plasma concentration was evident
and no direct relationship to the dose administered was
noted.
109
In this phase I clinical trial, one minor response was
seen at 30–35 mg/kg/day in a patient diagnosed with anaplas-
tic astrocytoma.
109
There was no evidence of efficacy in
patients with other tumor types including breast, prostate,
ovarian and other primary central nervous system malig-
nancies. However, the lack of efficacy in this trial may be
because the tumor types under study did not correspond to
those that are sensitive to lovastatin-induced apoptosis.
Two additional high-dose anti-cancer lovastatin trials have
been recently reported. Using the same dosing schedule, a
phase I–II trial targeted anaplastic astrocytoma and glioblas-
toma multiforme with lovastatin (20–30 mg/kg/day orally)
alone or in combination with radiation treatment.
110
Of the
nine patients treated with lovastatin alone, there was one
stable, one minor and one partial response. Of the nine
patients that were treated with both lovastatin and radiation,
there were two minor and two partial responses as determined
by standard clinical trial response criteria.
110
A phase II study
of high-dose lovastatin (35 mg/kg/day orally) was conducted
in patients with gastric adenocarcinoma.
111
Patients were
treated for 1 week on and then were off drug for 3 weeks
which resulted in one out of 14 patients with stable
response.
111
In all three trials reported to date, the high dose
was well tolerated with no neurological, hematological, liver
or renal toxicity observed; however, tumor response was
limited.
To evaluate the safety and efficacy of lovastatin in the con-
trol of AML blast counts, we initiated a trial of lovastatin in
high-count, drug-refractory AML patients and administered an
oral dose of 10–20 mg/kg/day for a 2 week dosing period fol-
lowed by 2 weeks off. However, due to drug-related toxicities
in these patients, including nausea and elevated levels of cre-
atine phosphokinase, the full regimen could not be adminis-
tered. An alternative approach to diminish these toxicity issues
and to allow for an assessment of efficacy, was to administer
a lower dose of lovastatin for a prolonged period of time. An
elderly female presenting with relapsed AML, whose blast
cells were sensitive to lovastatin-induced apoptosis in vitro,
82
was treated with twice the maximal recommended cholesterol
dose of lovastatin 160 mg/day (苲2 mg/kg/day) for 54 days.
161
This regimen was effective in managing blast counts during
the period of drug administration.
161
Remarkably, despite halt-
ing the administration of drug, the decreased blast counts per-
sisted for an additional 3 months.
161
Indeed, recent results of
a clinical trial showed that administration of pravastatin to
patients with hepatocellular carcinoma at the recommended
cholesterol dose 40 mg/day (苲0.5 mg/kg/day) in conjunction
with 5-fluorouracil, doubled the median time of survival for
these patients.
108
This suggests that the statins may be of value
in disease control when combined with standard therapeutic
approaches.
162–164
Moreover, efficacy may be improved when
statins are administered in a low-dose regimen over an
extended period of time. Further investigation is required to
determine the best regimen of treatment for each tumor type

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
514
SPOTLIGHT
Leukemia
Table 3 Summary of clinical trial results involving statins as anti-cancer agents
Trial Statin Dosing Tumor types Results
Thibault
et al
109
Lovastatin 2–45 mg/kg/day prostate, astrocytoma, Toxicity:
delivered for 1 week, glioblastoma, breast, low grade gastrointestinal dysfunction,
then 3 weeks off colorectal, ovary, musculoskeletal system, myalgia and muscle
sarcoma, lung weakness at 25 mg/kg/day; no hematological
toxicity
Response:
one of 12 patients with anaplastic astrocytoma
at 30–35 mg/kg/day achieved 45% reduction in
tumor size
Larner
et al
110
Lovastatin 30 mg/kg/day with and glioma Toxicity:
without radiation for no myalgia seen;
relapsed patients; 20, no neurological, hematological, liver or renal
25, 30 kg/kg/day with toxicity observed
partial brain radiation
Response:
for newly diagnosed
Lovastatin alone: 1 partial (decrease of 50% or
patients; dose
more tumor volume), 1 minor, 1 stable (less
delivered for 1 week,
than 25% increase or decrease in tumor
then 3 weeks off
volume) of nine patients;
Lovastatin and concurrent radiation: 2 minor
responses, 2 partial responses of nine patients
Kim
et al
111
Lovastatin 35 mg/kg/day for 1 gastric Toxicity:
week then 3 weeks adenocarcinoma gastrointestinal dysfunction, anorexia, mild
off; supplemented with nausea, myalgia and muscle weakness;
ubiquinone muscle weakness reversed with ubiquinone
supplementation;
no hematological toxicity
Response:
one patient of 14 patients assessed, presented
with stable disease for 16 weeks
Minden
et al
161
Lovastatin 40 mg twice daily (80 acute myelogenous Toxicity:
mg/day) for 12 days; leukemia ulcerative lesions; no nausea
40 mg four times daily
Response:
(160 mg/day) for 54
controlled blast counts for 3 months after taken
days
off lovastatin
Kawata
et al
108
Pravastatin 40 mg/day with hepatocellular Toxicity:
standard treatment of carcinoma no change in liver or hematological function or
transcatheter arterial frequency of muscle cramps compared to
embolization and 5- control group
fluorouracil
Response:
significant increase in median survival from 18
months
vs
9 months in control
whether it be administration of a low dose of statins over an
extended period of time or a high dose of statins which is
well-tolerated for shorter periods. Another approach may be
to administer a statin with high specific activity in driving
tumor cell death. Indeed, cerivastatin fulfills this criteria
95,96
and although it has been recently recalled from the market,
66
evaluating its efficacy as an anti-cancer agent in vivo may
warrant its reinstatement. Taken together, further testing of the
statins to fully evaluate their efficacy as a novel therapeutic
agent alone and in combination with other agents is merited.
Future considerations
Clearly, understanding the molecular mechanism of statin’s
anti-cancer action remains outstanding. This knowledge is
fundamental as it is critical to the clinical management of
patients. To date, the depletion of GGPP is the pivotal signal
that triggers sensitive tumor cell types to undergo apoptosis
following statin exposure. Delineating whether specific trans-
forming events contribute to tumor sensitivity as well as ident-
ifying the geranylgeranylated substrate(s) and their down-
stream pathways essential for the cytotoxic effects of statins
will mark a key advance. Moreover, further work to unravel
the contribution of P-gp to tumor sensitivity and the mechan-
istic association of lovastatin-induced apoptosis and differen-
tiation is essential. The outcome of such investigations will
provide mechanistic insight into the growth arrest and apop-
totic response upon exposure to statins and may uncover a
novel molecular target for therapeutic intervention. In
addition, molecular predictors of response may be identified
allowing for more effective stratification of patients. Finally,
with the mechanism well understood, a synergistic combi-
nation of agents can be designed to maximize statin efficacy
in vivo.
Another major area of investigation in this field, is to evalu-
ate and optimize the clinical utility of statins as anti-cancer
agents. The tumor types that are sensitive to statin-induced

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
515
SPOTLIGHT
apoptosis, as opposed to growth arrest, will probably rep-
resent the most attractive therapeutic targets for tumor eradi-
cation. Furthermore, as statins possess low cytotoxicity toward
non-transformed cells and high tumoricidal activity, the net
result will be the recovery and survival of normal cells while
transformed cells are eliminated. In comparison to other mol-
ecular targeted therapies that require local delivery, this agent
can be delivered systemically to the patient, due to its tumor-
specific apoptotic properties and minimal general toxicities.
3
The clinically achievable plasma concentration corresponds
to the dose range that can trigger tumor-specific apoptosis in
vitro. Experimental evidence suggests the exposure to statin
therapy in vivo may be maximized by administering statins at
a low dose for extended treatment times or at high doses for
a limited period. Synergistic effects of statins in combination
with traditional chemotherapeutic agents have been shown,
warranting the addition of lovastatin to drug cocktails. This
synergy may be due to statin down-regulation of bcl-2
expression which has been shown to potentiate therapeutic
response with other agents that repress bcl-2 such as anti-
sense bcl-2 and retinoic acid. Tracking this and other dis-
tinguishing features of statin-induced apoptosis in vivo will be
mechanistically instructive. Finally, statins may be effective in
cancer prevention and this aspect needs to be directly
addressed. Taken together, HMG-CoA reductase inhibitors
have a proven track record as safe and effective drugs and are
readily available for application to the cancer clinic. Clearly,
the efficacy of these well established inhibitors as novel anti-
cancer therapeutic agents requires immediate evaluation
through additional clinical trials.
Acknowledgements
We wish to thank our colleagues who generously contributed
data prior to publication. We also thank the Penn Lab for criti-
cal review of the manuscript. We apologize to those whose
contributions have not been cited due to space constraints.
Support from the Canadian Institutes of Health Research
(formerly the Medical Research Council of Canada) for an
operating grant (LZP), doctoral research award (WWW) and
postdoctoral fellowship (JD) and the Leukemia Lymphoma
Society (formerly the Leukemia Society of America) for a trans-
lational research program grant (LZP and MDM) is gratefully
acknowledged.
References
1 Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999;
187: 127–137.
2 Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure.
Bioessays 2000; 22: 1007–1017.
3 Penn LZ. Apoptosis modulators as cancer therapeutics. Curr Opin
Invest Drugs 2001; 2: 684–692.
4 Schimmer AD, Hedley DW, Penn LZ, Minden MD. Receptor and
mitochondrial-mediated apoptosis in acute leukemia – a trans-
lational review. Blood 2001; 98: 3541–3553.
5 Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical
pathways of caspase activation during apoptosis. Annu Rev Cell
Dev Biol 1999; 15: 269–290.
6 Ashkenazi A, Dixit VM. Apoptosis control by death and decoy
receptors. Curr Opin Cell Biol 1999; 11: 255–260.
7 Reed JC. Bcl-2 family proteins. Oncogene 1998; 17: 3225–3236.
8 Evan G, Littlewood T. A matter of life and cell death. Science
1998; 281: 1317–1322.
9 Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members
Leukemia
and the mitochondria in apoptosis. Genes Dev 1999; 13:
1899–1911.
10 Raff M. Cell suicide for beginners. Nature 1998; 396: 119–122.
11 Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases:
structure, activation, substrates, and functions during apoptosis.
Annu Rev Biochem 1999; 68: 383–424.
12 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;
100: 57–70.
13 Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer
chemotherapy. Exp Cell Res 2000; 256: 42–49.
14 Goldstein JL, Brown MS. Regulation of the mevalonate pathway.
Nature 1990; 343: 425–430.
15 Russell DW. Cholesterol biosynthesis and metabolism. Cardio-
vasc Drugs Ther 1992; 6: 103–110.
16 Olson RE, Rudney H. Biosynthesis of ubiquinone. Vitam Horm
1983; 40: 1–43.
17 Sinensky M. Recent advances in the study of prenylated proteins.
Biochim Biophys Acta 2000; 1484: 93–106.
18 Kabakoff BD, Doyle JW, Kandutsch AA. Relationships among
dolichyl phosphate, glycoprotein synthesis, and cell culture
growth. Arch Biochem Biophys 1990; 276: 382–389.
19 Farnier M, Davignon J. Current and future treatment of hyperlipi-
demia: the role of statins. Am J Cardiol 1998; 82: 3J–10J.
20 Pedersen, TR. Pro and con: low-density lipoprotein cholesterol
lowering is and will be the key to the future of lipid management.
Am J Cardiol 2001; 87: 8–12.
21 Davidson MH. Safety profiles for the HMG-CoA reductase inhibi-
tors: treatment and trust. Drugs 2001; 61: 197–206.
22 Illingworth DR, Tobert JA. HMG-CoA reductase inhibitors. Adv
Protein Chem 2001; 56: 77–114.
23 Buchwald H. Cholesterol inhibition, cancer, and chemotherapy.
Lancet 1992; 339: 1154–1156.
24 Larsson O. HMG-CoA reductase inhibitors: role in normal and
malignant cells. Crit Rev Oncol Hematol 1996; 22: 197–212.
25 Elson CE, Peffley DM, Hentosh P, Mo H. Isoprenoid-mediated
inhibition of mevalonate synthesis: potential application to can-
cer. Proc Soc Exp Biol Med 1999; 221: 294–311.
26 Kawata S, Takaishi K, Nagase T, Ito N, Matsuda Y, Tamura S,
Matsuzawa Y, Tarui S. Increase in the active form of 3-hydroxy-
3-methylglutaryl coenzyme A reductase in human hepatocellular
carcinoma: possible mechanism for alteration of cholesterol
biosynthesis. Cancer Res 1990; 50: 3270–3273.
27 Harwood HJ Jr, Alvarez IM, Noyes WD, Stacpoole PW. In vivo
regulation of human leukocyte 3-hydroxy-3-methylglutaryl coen-
zyme A reductase: increased enzyme protein concentration and
catalytic efficiency in human leukemia and lymphoma. J Lipid
Res 1991; 32: 1237–1252.
28 Vitols S, Norgren S, Juliusson G, Tatidis L, Luthman, H. Multilevel
regulation of low-density lipoprotein receptor and 3-hydroxy-3-
methylglutaryl coenzyme A reductase gene expression in normal
and leukemic cells. Blood 1994; 84: 2689–2698.
29 Caruso MG, Notarnicola M, Santillo M, Cavallini A, Di Leo A.
Enhanced 3-hydroxy-3-methyl-glutaryl coenzyme A reductase
activity in human colorectal cancer not expressing low density
lipoprotein receptor. Anticancer Res 1999; 19: 451–454.
30 Hentosh P, Yuh SH, Elson CE, Peffley DM. Sterol-independent
regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase
in tumor cells. Mol Carcinog 2001; 32: 154–166.
31 Bennis F, Favre G, Le Gaillard F, Soula G. Importance of meva-
lonate-derived products in the control of HMG-CoA reductase
activity and growth of human lung adenocarcinoma cell line
A549. Int J Cancer 1993; 55: 640–645.
32 Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors and the risk of cancer: a nested
case-control study. Arch Intern Med 2000; 160: 2363–2368.
33 Lovastatin Study Groups I through IV. Lovastatin 5-year safety
and efficacy study. Arch Intern Med 1993; 153: 1079–1087.
34 Narisawa T, Fukaura Y, Terada K, Umezawa A, Tanida N, Yaz-
awa K, Ishikawa C. Prevention of 1,2-dimethylhydrazine-induced
colon tumorigenesis by HMG-CoA reductase inhibitors, pravasta-
tin and simvastatin, in ICR mice. Carcinogenesis 1994; 15:
2045–2048.
35 Narisawa T, Fukaura Y, Tanida N, Hasebe M, Ito M, Aizawa R.
Chemopreventive efficacy of low dose of pravastatin, an HMG-
CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
516
SPOTLIGHT
Leukemia
colon carcinogenesis in ICR mice. Tohoku J Exp Med 1996; 180:
131–138.
36 Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive
inhibitors of HMG-CoA reductase. Pharmacol Res 1995; 31:
9–27.
37 Hanefeld M, Deslypere JP, Ose L, Durrington PN, Farnier M,
Schmage N. Efficacy and safety of 300 micrograms and 400
micrograms cerivastatin once daily in patients with primary hyp-
ercholesterolaemia: a multicentre, randomized, double-blind,
placebo-controlled study. J Int Med Res 1999; 27: 115–129.
38 Thompson GR, Naoumova RP. Novel lipid-regulating drugs.
Expert Opin Invest Drugs 2000; 9: 2619–2628.
39 Farmer JA, Torre-Amione G. Comparative tolerability of the
HMG-CoA reductase inhibitors. Drug Safety 2000; 23: 197–213.
40 Alberts AW, MacDonald JS, Till AE, Tobert JA. Lovastatin. Car-
diovasc Drug Rev 1989; 7: 89–109.
41 Plosker GL, McTavish D. Simvastatin. A reappraisal of its phar-
macology and therapeutic efficacy in hypercholesterolaemia.
Drugs 1995; 50: 334–363.
42 Haria M, McTavish D. Pravastatin. A reappraisal of its pharmaco-
logical properties and clinical effectiveness in the management
of coronary heart disease. Drugs 1997; 53: 299–336.
43 Plosker GL, Wagstaff AJ. Fluvastatin: a review of its pharma-
cology and use in the management of hypercholesterolaemia.
Drugs 1996; 51: 433–459.
44 Malinowski JM. Atorvastatin: a hydroxymethylglutaryl-coenzyme
A reductase inhibitor. Am J Health Syst Pharm 1998; 55: 2253–
2267; quiz 2302–2253.
45 Bischoff H, Angerbauer R, Bender J, Bischoff E, Faggiotto A, Petz-
inna D, Pfitzner J, Porter MC, Schmidt D, Thomas G. Cerivastatin:
pharmacology of a novel synthetic and highly active HMG- CoA
reductase inhibitor. Atherosclerosis 1997; 135: 119–130.
46 McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A,
Schneck D, Smith G, Warwick M. Preclinical and clinical phar-
macology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor. Am J Cardiol 2001; 87: 28–32.
47 Kajinami K, Mabuchi H, Saito Y. NK-104: a novel synthetic
HMG-CoA reductase inhibitor. Expert Opin Invest Drugs 2000;
9: 2653–2661.
48 Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J. Crystal struc-
ture of the catalytic portion of human HMG-CoA reductase:
insights into regulation of activity and catalysis. EMBO J 2000;
19: 819–830.
49 Istvan ES, Deisenhofer J. Structural mechanism for statin inhi-
bition of HMG-CoA reductase. Science 2001; 292: 1160–1164.
50 Tang BK, Kalow W. Variable activation of lovastatin by hydro-
lytic enzymes in human plasma and liver. 4. Eur J Clin Pharmacol
1995; 47: 449–451.
51 Mauro VF. Clinical pharmacokinetics and practical applications
of simvastatin. Clin Pharmacokinet 1993; 24: 195–202.
52 Lennernas H, Fager G. Pharmacodynamics and pharmacokinet-
ics of the HMG-CoA reductase inhibitors. Similarities and differ-
ences. Clin Pharmacokinet 1997; 32: 403–425.
53 Muck W. Clinical pharmacokinetics of cerivastatin. Clin Pharma-
cokinet 2000; 39: 99–116.
54 Hanefeld M. Clinical rationale for rosuvastatin, a potent new
HMG-CoA reductase inhibitor. Int J Clin Pract 2001; 55: 399–
405.
55 Bottorff M, Hansten P. Long-term safety of hepatic hydroxyme-
thyl glutaryl coenzyme A reductase inhibitors: the role of metab-
olism-monograph for physicians. Arch Intern Med 2000; 160:
2273–2280.
56 Bischoff KM, Rodwell VW. Biosynthesis and characterization of
(S)- and (R)-3-hydroxy-3-methylglutaryl coenzyme A. Biochem
Med Metab Biol 1992; 48: 149–158.
57 Moghadasian MH. Clinical pharmacology of 3-hydroxy-3-
methylglutaryl coenzyme A reductase inhibitors. Life Sci 1999;
65: 1329–1337.
58 Brown MS, Goldstein JL. A receptor-mediated pathway for chol-
esterol homeostasis. Science 1986; 232: 34–47.
59 Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors
and myotoxicity. Drug Safety 2000; 22: 441–457.
60 Bogman K, Peyer AK, Torok M, Kusters E, Drewe J. HMG-CoA
reductase inhibitors and P-glycoprotein modulation. Br J Pharma-
col 2001; 132: 1183–1192.
61 Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal
failure associated with cerivastatin- gemfibrozil combination
therapy (see comments). Am J Cardiol 1999; 83: 1146.
62 Wang E. Casciano CN, Clement RP, Johnson WW. HMG-CoA
reductase inhibitors (statins) characterized as direct inhibitors of
P-glycoprotein. Pharm Res 2001; 18: 800–806.
63 Wu X, Whitfield LR, Stewart BH. Atorvastatin transport in the
Caco-2 cell model: contributions of P- glycoprotein and the pro-
ton-monocarboxylic acid co-transporter. Pharm Res 2000; 17:
209–215.
64 Insull W Jr, Isaacsohn J, Kwiterovich P, Ra P, Brazg R, Dujovne C,
Shan M, Shugrue-Crowley E, Ripa S, Tota R. Efficacy and safety of
cerivastatin 0.8 mg in patients with hypercholesterolaemia: the
pivotal placebo-controlled clinical trial. Cerivastatin Study
Group. J Int Med Res 2000; 28: 47–68.
65 Cozza KL, Armstrong SC. 3A4. In: Hales RE (ed.). Cytochrome
p450 System:Drug Interaction Principles for Medical Practice.
American Psychiatric Publishing: Washington, DC, 2001: pp
47–68.
66 Weber W. Drug firm withdraws statin from the market. Lancet
2001; 358: 568.
67 Keyomarsi K, Sandoval L, Band V, Pardee AB. Synchronization
of tumor and normal cells from G1 to multiple cell cycles by
lovastatin. Cancer Res 1991; 51: 3602–3609.
68 Jakobisiak M, Bruno S, Skierski JS, Darzynkiewicz Z. Cell cycle-
specific effects of lovastatin. Proc Natl Acad Sci USA 1991; 88:
3628–3632.
69 Gray-Bablin J, Rao S, Keyomarsi K. Lovastatin induction of
cyclin-dependent kinase inhibitors in human breast cells occurs
in a cell cycle-independent fashion. Cancer Res 1997; 57:
604–609.
70 Hengst L, Dulic V, Slingerland JM, Lees E, Reed SI. A cell cycle-
regulated inhibitor of cyclin-dependent kinases. Proc Natl Acad
Sci USA 1994; 91: 5291–5295.
71 Wachtershauser A, Akoglu B, Stein J. HMG-CoA reductase
inhibitor mevastatin enhances the growth inhibitory effect of
butyrate in the colorectal carcinoma cell line Caco-2. Carcino-
genesis 2001; 22: 1061–1067.
72 Lee SJ, Ha MJ, Lee J, Nguyen P, Choi YH, Pirnia F, Kang WK,
Wang XF, Kim SJ, Trepel JB. Inhibition of the 3-hydroxy-3-
methylglutaryl-coenzyme A reductase pathway induces p53-
independent transcriptional regulation of p21(WAF1/CIP1) in
human prostate carcinoma cells. J Biol Chem 1998; 273:
10618–10623.
73 Rao S, Lowe M, Herliczek TW, Keyomarsi K. Lovastatin mediated
G1 arrest in normal and tumor breast cells is through inhibition
of CDK2 activity and redistribution of p21 and p27, independent
of p53. Oncogene 1998; 17: 2393–2402.
74 Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K.
Lovastatin-mediated G1 arrest is through inhibition of the protea-
some, independent of hydroxymethyl glutaryl-CoA reductase.
Proc Natl Acad Sci USA 1999; 96: 7797–7802.
75 Wojcik C, Bury M, Stoklosa T, Giermasz A, Feleszko W, Mlynar-
czuk I, Pleban E, Basak G, Omura S, Jakobisiak M. Lovastatin
and simvastatin are modulators of the proteasome. Int J Biochem
Cell Biol 2000; 32: 957–965.
76 Gardner RG, Hampton RY. A highly conserved signal controls
degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-
CoA) reductase in eukaryotes. J Biol Chem 1999; 274: 31671–
31678.
77 Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier
JP, Soria J, Soria C. Cerivastatin, an inhibitor of HMG-CoA
reductase, inhibits the signaling pathways involved in the invas-
iveness and metastatic properties of highly invasive breast cancer
cell lines: an in vitro study. Carcinogenesis 2001; 22: 1139–
1148.
78 Masters BA, Palmoski MJ, Flint OP, Gregg RE, Wang-Iverson D,
Durham SK. In vitro myotoxicity of the 3-hydroxy-3-methylgluta-
ryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and
simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl
Pharmacol 1995; 131: 163–174.
79 Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ, Kamel-Reid S,
Freedman MH, Yeger H, Penn LZ. Differential sensitivity of vari-
ous pediatric cancers and squamous cell carcinomas to lovasta-

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
517
SPOTLIGHT
tin-induced apoptosis: therapeutic implications. Clin Cancer Res
2001; 7: 158–167.
80 Perez-Sala D, Mollinedo F. Inhibition of isoprenoid biosynthesis
induces apoptosis in human promyelocytic HL-60 cells. Biochem
Biophys Res Commun 1994; 199: 1209–1215.
81 Newman A, Clutterbuck RD, Powles RL, Millar JL. Selective inhi-
bition of primary acute myeloid leukaemia cell growth by simva-
statin. Leukemia 1994; 8: 2023–2029.
82 Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger
H, Freedman MH, Minden MD, Penn LZ. Increased sensitivity
of acute myeloid leukemias to lovastatin-induced apoptosis: A
potential therapeutic approach. Blood 1999; 93: 1308–1318.
83 Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H.
Lovastatin-induced apoptosis of human medulloblastoma cell
lines in vitro. J Neurooncol 1999; 42: 1–11.
84 Rubins JB, Greatens T, Kratzke RA, Tan AT, Polunovsky VA, Bit-
terman P. Lovastatin induces apoptosis in malignant mesotheli-
oma cells. Am J Respir Crit Care Med 1998; 157: 1616–1622.
85 Muller C, Bockhorn AG, Klusmeier S, Kiehl M, Roeder C, Kalthoff
H, Koch OM. Lovastatin inhibits proliferation of pancreatic can-
cer cell lines with mutant as well as with wild-type K-ras onco-
gene but has different effects on protein phosphorylation and
induction of apoptosis. Int J Oncol 1998; 12: 717–723.
86 Dimitroulakos J, Yeger H. HMG-CoA reductase mediates the bio-
logical effects of retinoic acid on human neuroblastoma cells:
lovastatin specifically targets P-glycoprotein-expressing cells. Nat
Med 1996; 2: 326–333.
87 Jones KD, Couldwell WT, Hinton DR, Su Y, He S, Anker L, Law
RE. Lovastatin induces growth inhibition and apoptosis in human
malignant glioma cells. Biochem Biophys Res Commun 1994;
205: 1681–1687.
88 Marcelli M, Cunningham GR, Haidacher SJ, Padayatty SJ, Sturgis
L, Kagan C, Denner L. Caspase-7 is activated during lovastatin-
induced apoptosis of the prostate cancer cell line LNCaP. Cancer
Res 1998; 58: 76–83.
89 Ghosh PM, Ghosh-Choudhury N, Moyer ML, Mott GE, Thomas
CA, Foster BA, Greenberg NM, Kreisberg JI. Role of RhoA acti-
vation in the growth and morphology of a murine prostate tumor
cell line. Oncogene 1999; 18: 4120–4130.
90 Park C, Lee I, Kang WK. Lovastatin-induced E2F-1 modulation
and its effect on prostate cancer cell death. Carcinogenesis 2001;
22: 1727–1731.
91 Han Z, Wyche JH. Lovastatin induces apoptosis in metastatic
ovarian cell line. Cell Death Differ 1996; 3: 223–228.
92 Park WH, Lee YY, Kim ES, Seol JG, Jung C W, Lee CC, Kim BK.
Lovastatin-induced inhibition of HL-60 cell proliferation via cell
cycle arrest and apoptosis. Anticancer Res 1999; 19: 3133–3140.
93 Kim JS, Pirnia F, Choi YH, Nguyen PM, Knepper B, Tsokos M,
Schulte TW, Birrer MJ, Blagosklonny MV, Schaefer O, Mushinski
JF, Trepel JB. Lovastatin induces apoptosis in a primitive neuroec-
todermal tumor cell line in association with RB down-regulation
and loss of the G1 checkpoint. Oncogene 2000; 19: 6082–6090.
94 Marom M, Ben-Baruch G, Roitelman J, Kloog Y. Lack of corre-
lation between 3-hydroxy-3-methylglutaryl coenzyme A
reductase activity and lovastatin resistance in nerve growth factor
treated PC-12 cells. Cell Mol Neurobiol 1994; 14: 119–132.
95 Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn
LZ. Cerivastatin triggers tumor-specific apoptosis with higher
efficacy than lovastatin. Clin Cancer Res 2001; 7: 2067–2075.
96 Feleszko W, Mlynarczuk I, Nowis D. In vitro antitumor activity
of cerivastatin, a novel and potent HMG-CoA reductase inhibitor.
FEBS Lett 2001; 503: 219–220.
97 Luskey KL, Faust JR, Chin DJ, Brown MS, Goldstein JL. Amplifi-
cation of the gene for 3-hydroxy-3-methylglutaryl coenzyme A
reductase, but not for the 53-kDa protein, in UT-1 cells. J Biol
Chem 1983; 258: 8462–8469.
98 Ravid T, Avner R, Polak-Charcon S, Faust JR, Roitelman J.
Impaired regulation of 3-hydroxy-3-methylglutaryl-coenzyme A
reductase degradation in lovastatin-resistant cells. J Biol Chem
1999; 274: 29341–29351.
99 Kikuchi T, Nagata Y, Abe T. In vitro and in vivo antiproliferative
effects of simvastatin, an HMG-CoA reductase inhibitor, on
human glioma cells. J Neurooncol 1997; 34: 233–239.
100 Choi JW, Jung SE. Lovastatin-induced proliferation inhibition and
Leukemia
apoptosis in C6 glial cells. J Pharmacol Exp Ther 1999; 289:
572–579.
101 Bouterfa HL, Sattelmeyer V, Czub S, Vordermark D, Roosen K,
Tonn JC. Inhibition of Ras farnesylation by lovastatin leads to
downregulation of proliferation and migration in primary cul-
tured human glioblastoma cells. Anticancer Res 2000; 20:
2761–2771.
102 Agarwal B, Rao CV, Bhendwal S, Ramey WR, Shirin H, Reddy
BS, Holt PR. Lovastatin augments sulindac-induced apoptosis in
colon cancer cells and potentiates chemopreventive effects of
sulindac. Gastroenterology 1999; 117: 838–847.
103 Wang W, Macaulay RJ. Mevalonate prevents lovastatin-induced
apoptosis in medulloblastoma cell lines. Can J Neurol Sci 1999;
26: 305–310.
104 Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD, Penn
LZ. Blocking protein geranylgeranylation is essential for lovastat-
in- induced apoptosis of human acute myeloid leukemia cells.
Leukemia 2001; 15: 1398–1407.
105 Newman A, Clutterbuck RD, DeLord C, Powles RL, Catovsky D,
Millar JL. The sensitivity of leukemic bone marrow to simvastatin
is lost at remission: a potential purging agent for autologous bone
marrow transplantation. J Invest Med 1995; 43: 269–274.
106 Newman A, Clutterbuck RD, Powles RL, Catovsky D, Millar JL.
A comparison of the effect of the 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovas-
tatin and pravastatin on leukaemic and normal bone marrow pro-
genitors. Leuk Lymphoma 1997; 24: 533–537.
107 Clutterbuck RD, Millar BC, Powles RL, Newman A, Catovsky D,
Jarman M, Millar JL. Inhibitory effect of simvastatin on the pro-
liferation of human myeloid leukaemia cells in severe combined
immunodeficient (SCID) mice. Br J Haematol 1998; 102: 522–
527.
108 Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada
M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin
on survival in patients with advanced hepatocellular carcinoma.
A randomized controlled trial. Br J Cancer 2001; 84: 886–891.
109 Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl
RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE.
Phase I study of lovastatin, an inhibitor of the mevalonate path-
way, in patients with cancer. Clin Cancer Res 1996; 2: 483–491.
110 Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M. A phase
I–II trial of lovastatin for anaplastic astrocytoma and glioblastoma
multiforme. Am J Clin Oncol 1998; 21: 579–583.
111 Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, Park CH,
Kang WK. Phase II study of high-dose lovastatin in patients with
advanced gastric adenocarcinoma. Invest New Drugs 2001; 19:
81–83.
112 Dimitroulakos J, Thai S, Wasfy GH, Hedley DW, Minden MD,
Penn LZ. Lovastatin induces a pronounced differentiation
response in acute myeloid leukemias. Leuk Lymphoma 2000; 40:
167–178.
113 Agarwal B, Bhendwal S, Halmos B, Moss SF, Ramey WG, Holt
PR. Lovastatin augments apoptosis induced by chemotherapeutic
agents in colon cancer cells. Clin Cancer Res 1999; 5: 2223–
2229.
114 Schmidt F, Groscurth P, Kermer M, Dichgans J, Weller M. Lovas-
tatin and phenylacetate induce apoptosis, but not differentiation,
in human malignant glioma cells. Acta Neuropathol (Berl) 2001;
101: 217–224.
115 Wang IK, Lin-Shiau SY, Lin JK. Induction of apoptosis by lovasta-
tin through activation of caspase-3 and DNase II in leukaemia
HL-60 cells. Pharmacol Toxicol 2000; 86: 83–91.
116 Prendergast GC. Farnesyltransferase inhibitors: antineoplastic
mechanism and clinical prospects. Curr Opin Cell Biol 2000; 12:
166–173.
117 Jani JP, Specht S, Stemmler N, Blanock K, Singh SV, Gupta V,
Katoh A. Metastasis of B16F10 mouse melanoma inhibited by
lovastatin, an inhibitor of cholesterol biosynthesis. Invasion Met-
astasis 1993; 13: 314–324.
118 Alonso DF, Farina HG, Skilton G, Gabri MR, De Lorenzo MS,
Gomez DE. Reduction of mouse mammary tumor formation and
metastasis by lovastatin, an inhibitor of the mevalonate pathway
of cholesterol synthesis. Breast Cancer Res Treat 1998; 50: 83–
93.
119 Matar P, Rozados VR, Binda MM, Roggero EA, Bonfil RD,

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
518
SPOTLIGHT
Leukemia
Scharovsky OG. Inhibitory effect of Lovastatin on spontaneous
metastases derived from a rat lymphoma. Clin Exp Metastasis
1999; 17: 19–25.
120 Matar P, Rozados VR, Roggero EA, Scharovsky OG. Lovastatin
inhibits tumor growth and metastasis development of a rat fibro-
sarcoma. Cancer Biother Radiopharm 1998; 13: 387–393.
121 Wong B, Lumma WC, Smith AM, Sisko JT, Wright SD, Cai TQ.
Statins suppress THP-1 cell migration and secretion of matrix
metalloproteinase 9 by inhibiting geranylgeranylation. J Leukoc
Biol 2001; 69: 959–962.
122 Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo
H, Nakamura H. Inhibition of epidermal growth factor-induced
RhoA translocation and invasion of human pancreatic cancer
cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase
inhibitor. Cancer Res 2001; 61: 4885–4891.
123 DeClue JE, Vass WC, Papageorge AG, Lowy DR, Willumsen BM.
Inhibition of cell growth by lovastatin is independent of ras func-
tion. Cancer Res 1991; 51: 712–717.
124 Sebti SM, Tkalcevic GT, Jani, JP. Lovastatin, a cholesterol
biosynthesis inhibitor, inhibits the growth of human H-ras onco-
gene transformed cells in nude mice. Cancer Commun 1991; 3:
141–147.
125 Jani JP, Tkalcevic GT, Sebti SM. Lovastatin inhibits in vivo
tumour growth of H-ras and c-myc but not v-src oncogene-trans-
formed cells. Cell Pharmacol 1994; 1: 67–72.
126 Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks
M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis
in fibroblasts by c-myc protein. Cell 1992; 69: 119–128.
127 Holmberg M, Sandberg C, Nygren P, Larsson R. Effects of lovasta-
tin on a human myeloma cell line: increased sensitivity of a mul-
tidrug-resistant subline that expresses the 170 kDa P-glyco-
protein. Anticancer Drugs 1994; 5: 598–600.
128 Hunakova L, Sedlak J, Sulikova M, Chovancova J, Duraj J, Chorv-
ath B. Human multidrug-resistant (MRP,p190) myeloid leukemia
HL-60/ADR cells in vitro: resistance to the mevalonate pathway
inhibitor lovastatin. Neoplasma 1997; 44: 366–369.
129 Maksumova L, Ohnishi K, Muratkhodjaev F, Zhang W, Pan L,
Takeshita A, Ohno R. Increased sensitivity of multidrug-resistant
myeloid leukemia cell lines to lovastatin. Leukemia 2000; 14:
1444–1450.
130 Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is
required for radiation-induced apoptosis in mouse thymocytes.
Nature 1993; 362: 847–849.
131 Kiener PA, Davis PM, Murray JL, Youssef S, Rankin BM, Kowala
M. Stimulation of inflammatory responses in vitro and in vivo by
lipophilic HMG-CoA reductase inhibitors. Int Immunopharmacol
2001; 1: 105–118.
132 Montero MT, Hernandez O, Suarez Y, Matilla J, Ferruelo AJ, Mar-
tinez-Botas J, Gomez-Coronado D, Lasuncion MA. Hydroxyme-
thylglutaryl-coenzyme A reductase inhibition stimulates caspase-
1 activity and Th1-cytokine release in peripheral blood mono-
nuclear cells. Atherosclerosis 2000; 153: 303–313.
133 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recog-
nized type of immunomodulator. Nat Med 2000; 6: 1399–1402.
134 Kwak BR, Mach F. Statins inhibit leukocyte recruitment: new evi-
dence for their anti- inflammatory properties. Arterioscler
Thromb Vasc Biol 2001; 21: 1256–1258.
135 Diomede L, Albani D, Sottocorno M, Donati MB, Bianchi M,
Fruscella P, Salmona M. In vivo anti-inflammatory effect of stat-
ins is mediated by nonsterol mevalonate products. Arterioscler
Thromb Vasc Biol 2001; 21: 1327–1332.
136 Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa
WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin
activates the protein kinase Akt and promotes angiogenesis in
normocholesterolemic animals. Nat Med 2000; 6: 1004–1010.
137 Satoh K, Ichihara K, Landon EJ, Inagami T, Tang H. 3-Hydroxy-
3-methylglutaryl-CoA reductase inhibitors block calcium-depen-
dent tyrosine kinase Pyk2 activation by angiotensin II in vascular
endothelial cells. Involvement of geranylgeranylation of small G
protein Rap1. J Biol Chem 2001; 276: 15761–15767.
138 Dechend R, Fiebeler A, Park JK, Muller DN, Theuer J, Mervaala
E, Bieringer M, Gulba D, Dietz R, Luft FC, Haller H. Amelioration
of angiotensin II-induced cardiac injury by a 3-hydroxy-3-
methylglutaryl coenzyme a reductase inhibitor. Circulation
2001; 104: 576–581.
139 Gotto AM Jr, Farmer JA. Pleiotropic effects of statins: do they
matter? Curr Opin Lipidol 2001; 12: 391–394.
140 Stark WW Jr, Blaskovich MA, Johnson BA, Qian Y, Vasudevan
A, Pitt B, Hamilton AD, Sebti SM, Davies P. Inhibiting geranyl-
geranylation blocks growth and promotes apoptosis in pulmon-
ary vascular smooth muscle cells. Am J Physiol 1998; 275:
L55–63.
141 Negre-Aminou P, van Vliet AK, van Erck M, van Thiel GC, van
Leeuwen RE, Cohen LH. Inhibition of proliferation of human
smooth muscle cells by various HMG-CoA reductase inhibitors;
comparison with other human cell types. Biochim Biophys Acta
1997; 1345: 259–268.
142 Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A,
Plaza JJ, Diaz C, Hernandez G, Egido J. 3-Hydroxy-3-methylglut-
aryl coenzyme a reductase and isoprenylation inhibitors induce
apoptosis of vascular smooth muscle cells in culture. Circ Res
1998; 83: 490–500.
143 Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiem-
ann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM. HMG-
CoA reductase inhibitors (statins) increase endothelial progenitor
cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001; 108:
391–397.
144 Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawa-
moto A, Walsh K, Isner JM, Asahara T. HMG-CoA reductase
inhibitor mobilizes bone marrow--derived endothelial progenitor
cells. J Clin Invest 2001; 108: 399–405.
145 Guo YS, Jin GF, Houston CW, Thompson JC, Townsend CM Jr.
Insulin-like growth factor-I promotes multidrug resistance in
MCLM colon cancer cells. J Cell Physiol 1998; 175: 141–148.
146 Bonapace IM, Addeo R, Altucci L, Cicatiello L, Bifulco M, Laezza
C, Salzano S, Sica V, Bresciani F, Weisz A. 17 beta-Estradiol
overcomes a G1 block induced by HMG-CoA reductase inhibi-
tors and fosters cell cycle progression without inducing ERK-1
and -2 MAP kinases activation. Oncogene 1996; 12: 753–763.
147 Addeo R, Altucci L, Battista T, Bonapace IM, Cancemi M, Cicati-
ello L, Germano D, Pacilio C, Salzano S, Bresciani F, Weisz A.
Stimulation of human breast cancer MCF-7 cells with estrogen
prevents cell cycle arrest by HMG-CoA reductase inhibitors.
Biochem Biophys Res Commun 1996; 220: 864–870.
148 Carlberg M, Larsson O. Stimulatory effect of PDGF on HMG-
CoA reductase activity and N-linked glycosylation contributes to
increased expression of IGF-1 receptors in human fibroblasts.
Exp Cell Res 1996; 223: 142–148.
149 Kawata S, Kakimoto H, Ishiguro H, Yamasaki E, Inui Y, Matsuz-
awa Y. Effect of pravastatin, a potent 3-hydroxy-3-methylglutaryl-
coenzyme A reductase inhibitor, on survival of AH130 hepa-
toma-bearing rats. Jpn J Cancer Res 1992; 83: 1120–1123.
150 Sumi S, Beauchamp RD, Townsend CM Jr, Uchida T, Murakami
M, Rajaraman S, Ishizuka J, Thompson, JC. Inhibition of pancre-
atic adenocarcinoma cell growth by lovastatin. Gastroenterology
1992; 103: 982–989.
151 Hawk MA, Cesen KT, Siglin JC, Stoner GD, Ruch RJ. Inhibition
of lung tumor cell growth in vitro and mouse lung tumor forma-
tion by lovastatin. Cancer Lett 1996; 109: 217–222.
152 Maltese WA, Defendini R, Green RA, Sheridan KM, Donley DK.
Suppression of murine neuroblastoma growth in vivo by mevino-
lin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coen-
zyme A reductase. J Clin Invest 1985; 76: 1748–1754.
153 Feleszko W, Mlynarczuk I, Balkowiec-Iskra EZ, Czajka A, Switaj
T, Stoklosa T, Giermasz A, Jakobisiak M. Lovastatin potentiates
antitumor activity and attenuates cardiotoxicity of doxorubicin
in three tumor models in mice. Clin Cancer Res 2000; 6:
2044–2052.
154 Feleszko W, Balkowiec EZ, Sieberth E, Marczak M, Dabrowska
A, Giermasz A, Czajka A, Jakobisiak, M. Lovastatin and tumor
necrosis factor-alpha exhibit potentiated antitumor effects against
Ha-ras-transformed murine tumor via inhibition of tumor-
induced angiogenesis. Int J Cancer 1999; 81: 560–567.
155 Feleszko W, Lasek W, Golab J, Jakobisiak M. Synergistic anti-
tumor activity of tumor necrosis factor-alpha and lovastatin
against MmB16 melanoma in mice. Neoplasma 1995; 42:69–
74.
156 Feleszko W, Jakobisiak M. Lovastatin augments apoptosis
induced by chemotherapeutic agents in colon cancer cells (letter;
comment). Clin Cancer Res 2000; 6: 1198–1199.

Statins trigger tumor-specific apoptosis
WW-L Wong
et al
519
SPOTLIGHT
157 Soma MR, Pagliarini P, Butti G, Paoletti R, Paoletti P, Fumagalli
R. Simvastatin, an inhibitor of cholesterol biosynthesis, shows a
synergistic effect with N,N⬘-bis(2-chloroethyl)-N-nitrosourea and
beta- interferon on human glioma cells. Cancer Res 1992; 52:
4348–4355.
158 Lishner M, Bar-Sef A, Elis A, Fabian I. Effect of simvastatin alone
and in combination with cytosine arabinoside on the prolifer-
ation of myeloid leukemia cell lines. J Invest Med 2001; 49:
319–324.
159 Holstein SA, Hohl RJ. Interaction of cytosine arabinoside and lov-
astatin in human leukemia cells. Leuk Res 2001; 25: 651–660.
160 Prasanna P, Thibault A, Liu L, Samid D. Lipid metabolism as a
target for brain cancer therapy: synergistic activity of lovastatin
and sodium phenylacetate against human glioma cells. J Neuro-
chem 1996; 66: 710–716.
161 Minden MD, Dimitroulakos J, Nohynek D, Penn LZ. Lovastatin
induced control of blast cell growth in an elderly patient with
acute myeloblastic leukemia. Leuk Lymphoma 2000; 40: 659–
662.
162 Miller AC, Kariko K, Myers CE, Clark EP, Samid D. Increased
radioresistance of EJras-transformed human osteosarcoma cells
Leukemia
and its modulation by lovastatin, an inhibitor of p21ras isoprenyl-
ation. Int J Cancer 1993; 53: 302–307.
163 Bernhard EJ, McKenna WG, Hamilton AD, Sebti SM, Qian Y,
Wu JM, Muschel RJ. Inhibiting Ras prenylation increases the
radiosensitivity of human tumor cell lines with activating
mutations of ras oncogenes. Cancer Res 1998; 58: 1754–1761.
164 Shack S, Gorospe M, Fawcett TW, Hudgins WR, Holbrook NJ.
Activation of the cholesterol pathway and Ras maturation in
response to stress. Oncogene 1999; 18: 6021–6028.
165 Mevacor (Lovastatin, MSD); Merck, Sharp and Dohme, Montreal,
Quebec, Canada.
166 Zocor (Simvastatin, MSD); Merck, Sharp and Dohme, Montreal,
Quebec, Canada.
167 Pravachol (Pravastatin sodium, MSD); Bristol Meyers Squibb,
Princeton, NJ, USA.
168 Lescol (Fluvastatin sodium, MSD); Novartis, Basel, Switzerland.
169 Lipitor (Atorvastatin calcium, MSD); Parke-Davis, Ann Arbor,
MI, USA.
170 Baycol/Lipobay (Cerivastatin sodium, MSD); Bayer, Wuppertal,
Germany.