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The Role of Statins in Cancer Prevention and Treatment

The Role of Statins in Cancer Prevention and Treatment

ABSTRACT: Statins inhibit the activity of the rate-limiting enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase, and are widely prescribed for lowering plasma lipid levels. Several statins have antitumor effects in experimental models, and observational studies suggest that this anticancer activity in the laboratory may translate into effective treatments and/or preventive strategies for certain human cancers. This paper reviews the laboratory and clinical evidence that statins have anticancer activity, discusses the possible mechanisms by which tumor growth may be inhibited by this class of drugs, and outlines strategies for the evaluation of these agents in the prevention and treatment of human cancers.

HMG-CoA reductase inhibitors
(or "statins") are US Food and
Drug Administration (FDA)-
approved for treating hypercholesteremia.
Members of this drug class
currently available in North America
are listed in Table 1.[1,2] Statins produce
reductions in low-density lipoprotein
(LDL) cholesterol of up to 60%
by inhibiting the rate-limiting step in
hepatic cholesterol biosynthesis and
have been shown to decrease cardiovascular
morbidity and mortality in
both primary and secondary prevention
studies (reviewed in [3]). Beyond
lipid-lowering, however, the statins
have effects on numerous other biologic
pathways, suggesting that they
may be useful for treating conditions
other than cardiovascular disease (reviewed
in [4-6]). For example, statins
have antithrombotic and anti-inflammatory
activity that may account for
their apparent ability to decrease the
risk of venous thromboembolism and
ischemic stroke, prevent osteoporosis,
and retard the progression of multiple
sclerosis. In addition, they are
generating much interest in their anticancer
activity, which is the subject
of this review. The pleiotropic activities
of statins are summarized in
Table 2.[1,5,7-14]

General Information

Over 76 million prescriptions for
statins were filled in the United States
in 2000, making statins the most widely
prescribed drug class for lowering
cholesterol and among the most widely
prescribed of all drug classes. While
they all competitively inhibit the
enzyme HMG-CoA reductase, the six
statins currently available in North
America differ in their synthesis, structure,
potency, metabolism, and pharmacokinetic
and pharmacodynamic
properties (Table 1). These dissimilarities
may account for the observation
that the individual drugs seem to have
disparate anticancer activities.[15,16]

Biochemistry
Lovastatin, a mevinic acid derivative
produced by fermentation of
Aspergillus terreus, was the first statin
marketed in the United States for cholesterol-lowering. Pravastatin
(Pravachol) and simvastatin (Zocor)
are the two other fungal-derived,
"natural" statins. Fluvastatin (Lescol)
was the first entirely synthetic statin
and has been followed by atorvastatin
(Lipitor), cerivastatin, and rosuvastatin
(Crestor). Cerivastatin has been
voluntarily removed from the US market
because of its association with a
higher than expected number of fatal
cases of rhabdomyolysis.

All statins are competitive inhibitors
of HMG-CoA reductase to prevent
the conversion of HMG-CoA to
mevalonate (Figure 1). Disruption of
this step results in an overall decrease
in the amount of cholesterol produced
by the liver and, therefore, a lowering
of plasma cholesterol levels. Although
cholesterol is the most widely studied
product, several key intermediate
products of this biochemical pathway
are also affected by statins. It is the inhibition of these intermediates that
accounts for the panoply of biologic
effects that statins have beyond cholesterol
reduction.

Products of the cholesterol biosynthesis
pathway with particular relevance
to oncology include geranylgeranyl
pyrophosphate (GGPP) and farnesyl
pyrophosphate (FPP), which are used
by their respective transferase enzymes
for posttranslational modification
of certain cellular proteins. For
example, Ras requires the addition of
a farnesyl moiety for activity,[17] and
targeting this farnesylation step with
farnesyl transferase inhibitors is an
active area of cancer treatment investigation.
Similarly, Rho GTP-binding
proteins are involved in cell
signaling processes and require geranylgeranylation
for activity.[18] Inhibition
of Rho protein activity by
disruption of geranylgeranylation is
also a promising potential cancer treatment
strategy and is discussed below.

Pharmacology
The pharmacology of HMG CoA
reductase inhibitors has been reviewed
in detail recently.[1] The statins are
orally administered and are variably
absorbed from the gastrointestinal
tract with bioavailabilities ranging
from < 5% (lovastatin, simvastatin)to 25% (fluvastatin). The statins concentrate
in the liver, where they reduce
hepatic cholesterol synthesis,
resulting in upregulation of hepatic
LDL receptors, which in turn results
in increased clearance of LDL cholesterol
from plasma. Since statins
concentrate in the liver, little drug circulates
in plasma and that which does
circulate is highly protein bound.

Except for rosuvastatin, the statins
are extensively metabolized in the liver
to active (atorvastatin, lovastatin,
simvastatin) or inactive (fluvastatin,
pravastatin) metabolites. All statins
are eliminated predominantly by biliary
excretion into feces; however, the
elimination half-lives vary considerably
(Table 1). The statins differ in
their solubility properties; pravastatin
and rosuvastatin are hydrophilic,
whereas the remaining members of
the class are lipophilic. Pravastatin is
unique among the statins in that it is
not metabolized by the cytochrome
P450 system and hence has fewer potential
medication interactions than
other members of the class.

Toxicity
Statins have been used safely in millions
of people worldwide, but cerivastatin
was withdrawn from the US
market after postmarketing surveillance revealed a higher than expected incidence
of fatal rhabdomyolysis. Liver
and muscle are the primary targets of
statin toxicity. In large, randomized cardiovascular
clinical trials, elevations of
serum transaminase levels to greater
than three times normal were observed
in 1% to 3% of participants receiving
statins (reviewed in [19]). No study,
however, has demonstrated a significant
difference between statins and placebo
for serious hepatic adverse events.

All statins may be associated with
asymptomatic elevations of serum creatinine
kinase or with symptomatic
muscle injury (reviewed in [20,21]),
but the incidence of these events is low
(< 1% and 0.1%, respectively). Moreover,
in four major cardiovascular trials
involving over 50,000 participants,
no significant differences in the incidence
of muscle injury were observed
in the statin and placebo groups. Rhabdomyolysis
is a rare but potentially fatal
complication of statin use. Cerivastatin
accounted for nearly half of all reported
fatal rhabdomyolysis cases through
2001 (31 of 73 total cases), and the rate
of fatal rhabdomyolysis with cerivastatin
was 16 to 80 times greater than that
for any other statin. It must be noted,
however, that these 73 statin-associated
rhabdomyolysis deaths occurred
in the context of nearly 500,000,000
statin prescriptions dispensed, indicating
that serious muscle complications
due to these drugs are rare. Moreover,
the risk of muscle injury is highest when
statins are administered concurrently
with certain other medications that
increase plasma statin levels, including
fibric acid derivatives (eg, gemfibrozil),
azoles (eg, itraconazole
[Sporanox], fluconazole), erythromycin,
and some immunosuppressive
agents (eg, cyclosporine).

Do Statins Cause or
Prevent Cancer?

The results of toxicology studies in
animals raised the concern early on
that statins might cause cancer (reviewed
in [22]), and a meta-analysis of
cholesterol-reduction studies reported
a small but nonsignificant excess of
cancer deaths in participants treated
with cholesterol-lowering agents.[23]
As a result, later cardiovascular trials included cancer incidence as a secondary
end point, and multiple epidemiologic
investigations have been conducted
to assess the possibility that statins
might cause harm. Major human studies
in which the effect of statins on
cancer incidence has been evaluated
are summarized in Table 3.[24-44]

In general, statins are safe and well
tolerated by most people who take
them, and there is no persuasive evidence
linking these drugs to the development
of cancer in humans.
Neither the increase in breast cancer
cases seen in one study[26] nor the
small increased incidence of malignancy
in one elderly population[28]
has been replicated in several larger
investigations. Moreover, later metaanalyses
and epidemiologic studies do
not demonstrate an increased risk of
cancer (Table 3). On the contrary, the
preponderance of currently available
data suggests that statins may prevent
cancer. This was first hinted at in the
Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/
TexCAPS), in which lovastatin was
compared to placebo for the primary
prevention of cardiovascular disease, and a 50% reduction in new cases of
melanoma was observed in the treatment
group.[24] Results of subsequent
case-control studies further support
the hypothesis that statins prevent certain
malignancies, including melanoma,
and cancers of the breast, colon,
and possibly prostate.[37-40,44,45]

Do Statins Help Treat Cancer?Lovastatin and Brain Tumors
Lovastatin has been evaluated in a
phase I trial in which the maximum
tolerated dose was 25 mg/kg/d (in four
divided doses) administered on days
1 through 7 of a 28-day cycle.[46] The
dose-limiting toxicity was myopathy,
which was preventable by treatment
with ubiquinone (also known as coenzyme
Q), a downstream derivative of
mevalonate whose production is inhibited
by statins (see Figure 1). One partial
response was documented in a
patient with a high-grade glioma
among 88 patients treated in the study.

An ensuing phase I/II trial evaluated
lovastatin alone or combined with
radiation in patients with anaplastic astrocytoma
and glioblastoma multiforme.[
47] Patients with newly
diagnosed tumors received combinedmodality
treatment, and those with relapsed
disease were treated with the
statin alone. Cohorts of three patients
in the combined-modality group each received a lovastatin dose of 20, 25,
and 30 mg/kg/d for the first 7 days of
28-day cycles. No unexpected neurologic
toxicity was observed at any lovastatin
dose level. There were two minor
and two partial responses in this group
(response duration: 160-236 days) and
no complete responses. In nine patients
with relapsed tumors treated with the
drug alone at a dose of 30 mg/kg/d
using the same schedule, one patient
had a partial response lasting in excess
of 405 days, one had a minor response,
and one had stable disease. Lovastatin
was associated with little toxicity in
this study, and no patient discontinued
the drug due to adverse events. Although
two patients experienced episodes
of arthralgias (which readily
responded to treatment with analge-sics), no patients developed myopathy.

These studies suggest that lovastatin
is well-tolerated at high doses and
may have modest anticancer activity
in high-grade brain tumors. By contrast,
a phase II study of lovastatin
(35 mg/kg/d for 7 days repeated every
28 days) in advanced gastric cancer
demonstrated no responses among 16
patients.[48]

Effect of Administration Schedule
Although it is likely that statins, like
most anticancer agents, will be effective
in some tumor types but not others,
the intermittent administration schedule
employed in the studies above may
have been inappropriate and might lead
to the abandonment of a promising
agent prematurely. Laboratory investigations
point to a growth inhibitory mechanism of action for statins in cancer
(see below); thus, a continuous administration
schedule may be preferred.

For example, fluvastatin was administered
daily for 14 days every 4 weeks
in a phase I study with 12 pediatric
patients with refractory solid tumors.[
49] The maximum tolerated dose
of fluvastatin administered on this
schedule was 8 mg/kg/d, and despite the poor prognosis of this group of
patients, there were 6 partial responses
with two anaplastic astrocytoma patients
remaining alive 22 months after
initiating treatment. In another report, a
patient with relapsed acute myelogenous
leukemia (AML) treated with
lovastatin, 40 mg four times daily continuously
for 2 months, experienced a
decline in the peripheral blast count,
which persisted for an additional 3
months after stopping the drug.[50]

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