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Pharmacotherapy
Statins and cancer
L.V.A.M. Beex
Although proliferating malignant cells consume cholesterol, this may not completely explain
the observed inverse relation between plasma cholesterol levels and the incidence of cancer.
Results of studies and meta-analysis, investigating possible adverse effects of cholesterollowering therapy did not disclose any consistent promoting or preventive activity of statins
on the incidence of frequently occurring cancers. However, statin use may reduce the rate
of dedifferentiation and recurrence of established prostate and breast cancer. Furthermore, lipoprotein (-like) ligands for low- and high density lipoprotein receptors on tumour
cells can serve as carriers for targeted anti-cancer therapies.
(Belg J Med Oncol 2013:7(2):46-49)
Introduction
There is a well-known relationship between low
levels of cholesterol and an increased risk for dying
from cancer.1,2 The most important mechanism for
that is an increased consumption of cholesterol by
cancer cells.3 However, there remains a less understood weak relationship between low levels of cholesterol long before the onset of cancer, suggesting that
a causal connection is not completely excluded. So
the question remains whether lowering of cholesterol
levels by medical treatment could enhance the risk
for subsequent cancer. Cholesterol levels can be
lowered effectively by the use of statins.
Cholesterol synthesis and statins
The synthesis of cholesterol by the mevalonate
pathway is predominantly located in the liver but in
addition also in macrophages and other peripheral
cells. AcetylCoenzyme A (ACoA) and subsequently
beta-hydroxy-beta methylglutaryl CoA (HMG-CoA)
are formed from waste products of carbohydrates
and fatty acids. HMG-CoA is transformed into
HMG-CoA mevalonic acid, by the activity of HMGCoA reductase. After several more enzymatic steps,
HMG-CoA mevalonic acid is transformed into farnesyl pyrophosphate and thereafter converted to
cholesterol but also to other molecules, including
geranyl pyrophosphate. Both farnesyl pyrophos-
phate and geranyl pyrophosphate contribute to the
lipidation of cellular proteins (=prenylation), enabling
those proteins to attach the cell membrane for interaction with (proliferative) cell activity.4,5 The transport of cholesterol is carrier-bound by lipoproteins,
i.e. Low Density Lipoproteins (LDL) and High
Density Lipoproteins (HDL).
Statins are competitive antagonists of HMG-CoA
reductase and therefore can reduce the production
of cholesterol and other end products of the mevalonate pathway, and this occurs predominantly in
liver cells. Consequently, the production of LDLreceptors (LDLR) on the surface of hepatocytes is
upregulated, allowing the binding of LDL cholesterol
out of the blood with the decrease of LDL cholesterol
levels as a consequence. Moreover, statins may prevent
the synthesis of precursors of LDL in the liver. The
extensive use of statins has resulted in the decrease
of cardiovascular morbidity and mortality.6
Statins may have hydrophilic (atorvastatin, pravastatin, rosuvastatin) or lipophilic (simvastatin, fluvastatin, pitavastatin) properties. Hydrophilic statins are
more hepatocyte-specific (by active transport in those
cells) as compared to lipophilic statins and therefore have less general and cell-specific side-effects.7
Lipophilic statins also inhibit the production of
cholesterol and sterols in other cells, including cancer
cells. Some statins, especially the lipophylic statins
Author: L.V.A.M. Beex MD PhD, Department of medical oncology, Radboud University Nijmegen Medical Centre, Geert Grooteplein 8,
6500 HB Nijmegen, The Netherlands, tel: +31 24 361 88 00. e-mail: [email protected].
Conflict of interest: the author has nothing to disclose and indicates no potential conflict of interest.
Keywords: cancer, cholesterol, cholesterol receptors, mevalonate pathway, statins.
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pitavastatin and simvastatin and the hydrophilic rosuvastatin, can increase the levels of HDL cholesterol.8
Cancer and cholesterol metabolism
Cholesterol is of importance to the integrity of cellular membranes and to cellular signal transduction
processes and therefore may facilitate proliferation.
In cancer cells, LDL-receptors (LDL-R) may be excessively activated with an increased cellular metabolism of LDL cholesterol and a decrease of plasma
cholesterol levels as a consequence, which can often
be found in patients with cancer progression.3,9-12
In contrast to most normal cells, hepatocytes, but
cancer cells as well, are able to bind HDL-cholesterol
by appropriate HDL-receptors (i.e. Scavenger Receptor B1).13 HDL cholesterol is important for its role
in transporting cholesterol back to the liver cells.
HDL cholesterol has also anti-inflammatory, antioxidant and anti-thrombotic properties, favouring
the anti- atherogenic effects of this lipoprotein.7,8
Potentially, the presence of both receptor types in
cancer cells could suggest they might be involved
in the initiation and progression of cancer.
The increased availability of cholesterol receptors in
cancer cells is puzzling when taking the coincident
upregulation of the mevalonate pathway in those
cells into account. The latter has been observed by
increased levels of HMG-CoA reductase levels in
cancer cells.5 Llaverias et al have suggested that in
(breast)cancer cells the upregulated mevalonate
pathway primarily induces molecules for prenylation of cellular proteins and to a lesser extent for
the production of cholesterol. The lack of sufficient
cholesterol, not fulfilling the requirements for malignant cells, may therefore contribute to the increased
cholesterol receptor activity and subsequent cholesterol consumption.14
Statins and incidence of cancer
Based on suggestions of an increased cancer incidence with the use of statins, Thompson et al.
reviewed the available literature on this topic and
found five, mostly small and older studies, that were
compatible with these suggestions.15 An increased
incidence of cancer was found in particular when the
use of statins was combined with drugs inhibiting
the uptake of cholesterol, or in participants with the
lowest LDL-cholesterol levels. However, in six studies,
including three meta-analyses, no such relation was
found. In fact, in one of the included studies the use
of lipophylic (hydrophobic) statins was correlated
with a decreased incidence of breast cancer.16
Brugts et al. published a meta-analysis of ten trials
with in total 70,388 men and women who either
suffered from cardio-vascular disease (in 20% of
cases) or had an increased risk for cardio-vascular
disease, and who were randomised for statin use or
not. After a median observation time of four years,
a significant decrease in severe cardio-vascular
incidents and death was found (HR 0.81 and 0.88
respectively). However, the risk for cancer was about
equal in both groups (HR 0.97).17
Beneficial and adverse effects of statins were also
investigated by Baigent et al. In their reported metaanalysis no differences in cancer incidence or mortality were detected in 21 randomised trials comparing the use of statins versus placebo or no
therapy in 129,526 men and women. The median
observation times in the included studies ranged
from two to six years.18 In the same report, the
effects of high versus low dose statins on the
incidence of cancer in five trials did not disclose
any significant differences either.
More recently, the long-term effects of simvastatin
use, (a lipophylic statin) have been published.19
In the Heart Protection Study, which was first published in 2002, 15,454 men and 5082 women
at risk for cardiovascular disease were randomised
for the use of simvastatin 40 mg daily or placebo.20
After a median trial (and protocol medication) duration of 5,3 years, the 17,519 patients that were alive
at that time were allowed to continue with study
medication or to opt for simvastatin. Simvastatin
use reduced cardiovascular events and death with
23% and 18% respectively. After a follow-up period
of eleven years, no significant effect of statin use on
either cancer incidence or mortality was found. In
Table 1 an overview of the mentioned studies is given.
Although in individual studies the number of participating women may have been limited, the total
number of women in the meta-analysis and in the
Heart Protection Study were still considerable and
cancer incidence in both men and women, just as
in the total group, did not seem to be influenced by
the use of statins.17 The same was true when data were
analysed for different cancer types (gastrointestinal,
respiratory, breast, genitourinary and others).18,19
In a large prospective cohort study in 368 familydoctor practices in England and Wales over 225,000
new users of statins (without manifest cardiovascular
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Pharmacotherapy
Table 1. Statin use and cancer incidence.
Meta analysis
Number of
trials
Randomisation
Participants
(% women)
Follow-up
(median, yrs)
HR incidence
of cancer
Brugts et al.17
10
statin versus
placebo or usual
control
70.388
(34)
3.2-5.5
0.97
(0.89-1.05)
Baignent et al.18
21*
statin versus
placebo or no
therapy
129.526
(29)
2-6
1.00
(0.95-1.04)
Baignent et al.18
5
high versus low
dose statins
39.612
(19)
2-7
1.02
(0.89-1.10)
HPS19
1
simvastatin
versus placebo
20.536
(24)
11
0.98
(0.92-1.05)
HR death
by cancer
0.99
(0.91-1.09)
no difference
*Including 9 trials overlapping with analysis from Brugts et al.
HPS = Heart Protection Study
disease) and more than 1.7 million non-users were
followed for side-effects of therapy.21 After five years
of observation, statin users versus non-users proved
to have more severe myopathies, liver function abnormalities, acute renal insufficiency and cataract.
A comprehensive analysis of the effects of statins
on the incidence of cancer showed that the risk
for oesophageal cancer in statin users, both men
and women, was significantly lower. For stomach,
colon, lung, breast, renal cell, prostate cancer and
melanoma no significant interactions were found
with the use of statins.21
On the basis of these observations, one should not
be reluctant to prescribe statins as there are no indications for an increased risk to develop cancer. On the
other hand, there are no hard arguments to prescribe
statins to prevent cancer. However, the effects for
special target groups, e.g. patients with a metabolic
syndrome, may be different. The common occurrence
of adiposity in this syndrome, with consequently
higher levels of oestrogens, may for instance complicate interpretations of effects of the use of statins
for the risk of postmenopausal breast cancer.
Statins and recurrence of cancer
In a review article of Papadopoulos et al. the authors
point to different possible interactions of statins on
the development of prostate cancer.22 Direct reduction of cholesterol as a ligand for cell membrane
LDL cholesterol receptors may lead to tumour suppression. Low dosages of statins promote angiogenesis. For high doses, however, anti-angiogenic effects
have been reported. Statins may induce cell apoptosis.
The anti-inflammatory properties of statins may
reduce progression of prostate cancer. The clinical
importance of these effects remains unclear. However, lipophilic statins, such as simvastatin, have
proven to delay the progression of prostate carcinoma
to hormone independency.23,24 In a retrospective
study, the use of statins (n=236) at time of radical
prostatectomy correlated with a reduction of the
risk for biochemical (prostate-specific antigen, PSA)
recurrence with 30%.25 It was also found that the
metabolic syndrome behaves as a stimulating factor
in the progression of prostate cancer.26
In a prospective Danish study with over 18,000
women with primary breast cancer, 3,282 received
a prescription for statins. Especially the use of
simvastatin (lipophilic) was correlated with a 10%
reduction in the risk for relapse during ten years of
follow-up. For hydrophilic statins such a relationship was not found.27 In accordance with this, in
cell lines of well or poorly differentiated cancers,
simvastatin (lipophylic) proved to be more effective
in inhibiting cell proliferation as compared to
pravastatin (hydrophilic).28 In the 2012 November
edition of the N Engl J Med, Nielsen et al. describe
the effects of the use of statins for cancer-related
mortality in the Danish population. The authors
found a non dose-response reduction in cancerrelated mortality of up to 15% by users of statins for
all of thirteen cancer types, whereas for most of the
remaining fourteen cancer types the same trend was
found but differences in awareness for cancer, smoking
and concomitant medication betweenstatin users and
non-users may have compromised these results.29
Lipoprotein receptors as targets for
therapy
The (by statin use enhanced) increased production
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Key messages for clinical practice
1.
Patients with cancer may have low cholesterol levels by an increased cholesterol
consumption by cancer cells. The use of cholesterol-lowering statins does not
consistently increase or decrease the incidence of cancer but may be beneficial to
patients with established breast or prostate cancer, both by decreasing the availability
of plasma cholesterol and by interference with the cancer cell mevalonate pathway.
2.
Cholesterol receptors on tumour cells may serve as targets for anti-cancer therapy.
and activation of cholesterol receptors on cancer
cells also offers a possibility for attacking tumour cells.
LDL’s are already involved in the delivery of photo
sensitisers to tumour cells.30 The structure of HDL
also allows the transport of hydrophobic substances
through the body. HDL can bind to the aforementioned HDL receptors on tumour cells. So it may be
possible to carry appropriate chemotherapeutics
(e.g. paclitaxel) very effectively to tumour cells.31,32
HDL-cholesterol particles can also be used as nano
molecules, carrying RNA particles that interfere with
the production of (proliferating) proteins (small
interference RNA, siRNA), into cancer cells.33
5. Clendening JW, Penn LZ. Oncogene 2012; 31(48):4967-78.
6. Steinberg D. New Engl J Med 2008;359:1426-27.
7. Sirtori C. Pharmac Ther 1993;60:431-59.
8. Yamashita S, Tsubakio-Yamamoto K, Ohama T, et al. J Atheroscler
Thromb 2010;17:436-51.
9. Vitols S, Angelin B, Ericsson S, et al. Proc Natl Acad Sci USA 1990;87:
2598-602.
10.Graziani SR, Igreja FA, Hegg R, et al. Gynecol Oncol 2002;85:493-7.
11. Ades A, Carvalho JP, Graziani SR, et al. Gynecol oncol 2001;82:84-7.
12.Gorin A, Gabitova L, Astsaturov I. Current Opinion in Pharmacol 2012;1
2:1-7.
13.Lacko AG, Nair M, Ptokai L, et al. Expert Opin Drug Deliv 2007;4:665-75.
14.Llaverias G, Danilo C, Mercier I, et al. Am J Pathology 2011;178:402-12.
15.Thompson JS, Sood A, Arora R. Am J Ther 2010;17:e100-4.
Conclusion
No enhancing effects of statins on the incidence or
mortality of cancer during short and long observation
times have been found. Instead, statins may have
anti-cancer properties. However, until now this has not
been established for most types of cancer. Despite
this overall conclusion, it is worth mentioning that
especially lipophilic statins, such as simvastatin,
may have a protective effect for the occurrence of
oesophageal carcinoma and may reduce recurrences
of poorly differentiated prostate cancer or breast
cancer. In addition, there is a possibility that there
are also beneficial effects for patients with cancer
and the metabolic syndrome. Finally, lipoproteinreceptors on tumour cells may serve as targets for
LDL or HDL as transport molecules or as nano
particles in the treatment of cancer.
16. Cauley JA, McTiernan A, Rodabough RJ, et al. J Natl Cancer Inst
2006;98:700–7.
17. Brugts JJ, Yetgin T, Hoeks SE, et al. BMJ 2009; 338:b2376; BMJ Dutch
edition 2009;24:34-41.
18.Baignent C, Keech A, Kearney PM, et al. Lancet 2005;366:1267-78.
19.Heart Protection Study Collaborative Group, Bulbulia R, Bowman L,
Wallendszus K, Parish S, Armitage J, Peto R, Collins R. Lancet 2011;
378:2013-20.
20.Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
21.Hippisley-Cox J, Coupland C. BMJ 2010;340:c2197.
22.Papadopoulos G, Delakas D, Nakopoulou L, et al. Eur J Cancer 2011;
47:819-30.
23.Boudreau DM, Yu O, Johnson J. Expert Opin Drug Saf 2010;9(4):603-21.
24.Banez LL, Klink JC, Jachandran J, et al. Cancer Epidemiol Biomarkers
Prev 2010;19:722-8.
25.Hamilton RJ, Banez LL, Aronson WJ, et al. Cancer 2010;116:3389-98.
26.Flanagan J, Gray PK, Hahn N, et al. Ann Oncology 2011;22:801-7.
27. Ahern TP, Pedersen L, Tarp M, et al. J Natl Cancer Inst 2011;103(19):1461-8.
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