Statins Can Modulate Effectiveness of Antitumor Therapeutic

Statins Can Modulate E¡ectiveness
of AntitumorTherapeutic Modalities
Marek Jakobisiak and Jakub Golab

Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Banacha 1A,
02-097 Warsaw, Poland
Published online 15 June 2009 in Wiley InterScience (www.interscience.wiley.com).

DOI 10.1002/med.20162
.
Abstract: Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins
demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical
trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents.
However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular
events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with
many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation
of these interactions might affect the choice of treatment to be planned in cancer patients as some
combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a
cost of increased general toxicity. Some other combinations might induce either comparable or even
stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the
studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical
relevance of the findings is also discussed. & 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 1, 102–135, 2010
Key words: statins; chemotherapy; combination therapy; tumor
1. INTRODUCTION
Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors that have

been used in the clinic to ameliorate hypercholesterolemia. They have an excellent safety
profile, and exert beneficial effects in both primary and secondary prevention of cardiovas-
cular diseases. For this reason, statins are now among the most frequently prescribed drugs
(in the United Kingdom simvastatin is available without a prescription), and their use
steadily increases, particularly among the elderly. Statins inhibit the synthesis of mevalonic
acid (MA), which is an essential precursor of isoprenoid compounds (Fig. 1). The latter, in
turn, serve as precursors for numerous important biomolecules including cholesterol, do-
Contract grant sponsor: Ministry of Science and Higher Education; Contract grant number: N N405 302836; Contract grant
sponsor: The Medical University of Warsaw; Contract grant number: 1M19/N.
Correspondence to: Marek Jakobisiak, Department of Immunology, Center of Biostructure Research, The Medical University of
Warsaw,1 Banacha Street, F Building, 02-097 Warsaw, Poland, E-mail: marek.jakobisiak@wum.edu.pl
Medicinal Research Reviews, Vol. 30, No.1,102--135, 2010

& 2009 Wiley Periodicals, Inc.
COMBINATIONS OF STATINS WITH OTHER DRUGS K 103
Figure 1. Mevalonate pathway. The mevalonate pathway is used for the biosynthesis of isoprenoids. HMG-CoA (3-hydroxy
3-methylglutaryl-CoA) is converted to mevalonate by HMG-CoA reductase, the rate-limiting enzyme at the top of the mevalonate
pathway. Mevalonate is then converted to isopentenyl pyrophosphate, which is subsequently metabolized to farnesyl pyropho-
sphate through a series of enzymatic reactions. After addition of isopentenyl pyrophosphate, can be converted to geranylgeranyl
pyrophosphate (a 20-carbon isoprenoid), or alternatively farnesyl pyrophosphate can be converted to cholesterol or dolichol,
which is used for N-glycosylation of proteins. Geranylgeranyl pyrophosphate can be further processed to form ubiquinone
(coenzyme Q in humans), which participates in mitochondrial electron transfer. Farnesyl pyrophosphate and geranylgeranyl pyr-
ophosphate can be used in post-translational isoprenylation of cellular proteins. HMG-CoA reductase is the target of the choles-
terol-lowering statins. CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl. [Color figure can be viewed in the online issue, which
is available at www.interscience.wiley.com.]
lichol and ubiquinone, and are substrates for the post-translational modifications of many
proteins.1
Large, randomized clinical trials have largely dispelled any concerns associated with
potential carcinogenic effects of statins observed in early rodent studies.2 Quite contrary,
some studies have shown their chemopreventive effects in experimental tumor models.3 As
statins have been observed to have anti-inflammatory activity4,5 it cannot be excluded that
they could exert protective effects against inflammation-induced cancers. Such a possibility
has already been suggested in the ulcerative colitis-associated carcinogenesis in mice.6,7
Moreover, statins were recently demonstrated to reduce DNA damage induced by chemical
carcinogens8 and to accelerate DNA repair.9 The results of earlier clinical studies aimed to
elucidate the effects of statins on cancer incidence were inconsistent with some observations
suggesting decrease,10–16 at least for hydrophobic statins, i.e. simvastatin, lovastatin, and
Medicinal Research Reviews DOI 10.1002/med
104 K JAKOBISIAK AND GOLAB
fluvastatin, whereas other studies suggested some increase17,18 in cancer incidence. However,
more recent studies and several meta-analyses revealed no influence of statins on cancer risk
in humans,19–25 although, intriguingly, cell culture experiments with statins have shown their
cytostatic26–36 and cytotoxic7,33,35–46 effects against tumor cells.
Statins also displayed antitumor activity in experimental tumor models, inhibiting both
tumor growth7,30,33,42,44,47,48 and formation of metastases.47,49–56 Statins have been shown to
interfere with all essential steps of the metastatic process including attachment,50,51,57,58
motility,50 and invasion.34,49,52,54,55,59,60 They also have been shown to induce differentiation
of some61–63 but not of other64 tumor cells. Several studies revealed antiangiogenic activity of
statins in tumor models.7,55,65,66 However, proangiogenic effects of statins have also been
demonstrated67,68 probably depending on the dosage of statins used although other factors
cannot be excluded.69,70 Despite encouraging results of pre-clinical studies, clinical trials, so
far, have failed to demonstrate any significant therapeutic effects of statins in tumor pa-
tients71–76 although their peak plasma concentrations in tumor patients correspond to con-
centrations demonstrating antitumor effects in vitro. In a phase I study of lovastatin, given at
doses up to 45 mg/kg/day for 7 days its peak plasma concentrations were as high
as 3.9 mM.71 In another study, a short-term treatment with lovastatin at doses up to
415 mg/m2/day (which was well tolerated by all patients) maximum drug concentrations
reached 12.3 mM.77 These are the concentrations most frequently used in cell culture ex-
periments. Furthermore, statins have been found to influence the effectiveness of other
therapeutic modalities either potentiating or diminishing their antitumor effects. Now it is
too early to predict whether statins will ever be used intentionally in combination with
established tumor therapies. However, elderly cancer patients are frequently treated with
statins for their cardiovascular problems and interactions of statins with antitumor ther-
apeutic modalities are to be expected in many patients and deserve careful consideration.
2. COMBINATION WITH CHEMOTHERAPY
Chemotherapy is currently a mainstay of cancer therapy being either a primary cancer

treatment or an adjuvant to other treatment modalities, such as surgery. Moreover, some
chemotherapy regimens might be used in the neoadjuvant setting to reduce the size of the
primary tumor before its surgical resection. Recently approved monoclonal antibodies
(mAbs) and promising small-molecule inhibitors of particular signal transduction pathways
are usually administered concomitantly with chemotherapeutics. Any interactions of statins
with chemotherapeutics are then of particular interest as they may affect a very wide range of
cancer treatments.
A. Anthracyclines
Statins have been shown to potentiate antitumor effects of anthracyclines in cell culture
studies (Table I) and in tumor-bearing mice (Table II). Combination of lovastatin and
doxorubicin produced synergistic cytotoxic effects in mouse colon carcinoma,78 mouse
mammary adenocarcinoma, rat B-cell lymphoma cells,79 and additive effects in v-HRAS-
transformed mouse sarcoma and lung carcinoma cell line.78 In all five tumor models
lovastatin enhanced antitumor activity of doxorubicin in tumor-bearing animals.78,79
Lovastatin was also shown to potentiate synergistically antitumor effects of doxorubicin in
mouse melanoma cells and strengthen therapeutic activity of doxorubicin in mice injected
with melanoma cells.80 Simvastatin synergistically augmented doxorubicin cytotoxicity in
human rhabdomyosarcoma cells81 and enhanced cytotoxic effects of doxorubicin in human
Table I. Antitumor Effects of Anthracyclines Potentiated In Vitro by Statins
Interaction of drugs
Tumor cells Anthracycline Statin Type of effect in tumor cellsa References
85
Human MCF7/wt, MCF/adr, BT474, SK-BR-3 Epirubicin Fluvastatin Cytotoxic Synergistic in three out
breast carcinoma of four cell lines studied
84
Human primary AML cell cultures Daunorubicin Mevastatin Apoptosis Synergistic in 50%
of samples
86
Human AML-193 and KG-1 AML Daunorubicin Fluvastatin Cytotoxic Synergistic
86
Human AML-193 and KG-1 AML Idarubicin Fluvastatin Cytotoxic Synergistic
87
Human T4-2 breast carcinoma Doxorubicin Cerivastatin Cytostatic/ Synergistic
cytotoxic
87

Human MDA-MB-231 breast carcinoma Doxorubicin Cerivastatin Cytostatic/ Potentiation
cytotoxic
81
Human cultured rhabdomyosarcoma Doxorubicin Simvastatin Apoptosis Synergistic
83
Human p53-deficient H1299 NSCLC Doxorubicin Atorvastatin Cytostatic/ Potentiation
cytotoxic
82
Human KMB-5 myeloid leukemia Doxorubicin Simvastatin Apoptosis Synergistic
78
Mouse colon-26 adenocarcinoma Doxorubicin Lovastatin Cytostatic/ Synergistic
cytotoxic
78
Mouse Lewis lung carcinoma Doxorubicin Lovastatin Cytostatic/ Potentiation
cytotoxic
78
Mouse v-HRAS-transformed NIH-3T3 Doxorubicin Lovastatin Cytostatic/ Potentiation
cytotoxic
80
Mouse B16F10 melanoma Doxorubicin Lovastatin Apoptosis Synergistic
79
Rat L-TACB B-cell lymphoma and mouse Doxorubicin Lovastatin Apoptosis Synergistic
M-406 mammary adenocarcinoma
COMBINATIONS OF STATINS WITH OTHER DRUGS
Abbreviations: AML, acute myeloid leukemia; NSCLC, non-small cell lung cancer.
a
When interaction was not determined as being synergistic, the term ‘‘potentiation’’ was used.
105 K
Table II. Antitumor Effects of Various Therapeutic Modalities Potentiated by Statins in

Experimental Animals
Tumor Animal Therapy Statin References

78
Colon-26 adenocarcinoma Mice Doxorubicin Lovastatin
78
Lewis lung carcinoma Mice Doxorubicin Lovastatin
78
v-HRAS-transformed NIH-3T3 sarcoma Mice Doxorubicin Lovastatin
79
M-406 mammary adenocarcinoma Mice Doxorubicin Lovastatin
80
MmB16 melanoma Mice Doxorubicin Lovastatin
79
L-TACB B-cell lymphoma Rat Doxorubicin Lovastatin
123
MmB16 melanoma Mice Cisplatin Lovastatin
144
Human prostate cancer PC-3 SCID mice Celecoxib Atorvastatin
163
Panc02 pancreatic carcinoma Mice Pamidronate Lovastatin
172
Lewis lung carcinoma Mice Tributyrin Lovastatin
176
MH134 hepatocellular carcinoma Mice Enzastaurin Lovastatin
182
C6 astrocytoma Rats Carmustine Simvastatin
65
v-Ha-ras-transformed NIH-3T3 sarcoma Mice TNF Lovastatin
211
MmB16 melanoma Mice TNF Lovastatin
198
B16F10 melanoma Mice d-g-Tocotrienol Lovastatin
TNF, tumor necrosis factor.
myeloid leukemia cell line.82 Atorvastatin sensitized human non-small cell lung cancer cells
to doxorubicin83 and mevastatin sensitized human primary acute myeloid leukemia
(AML) cells to daunorubicin.84 Fluvastatin was synergistic with epirubicin in three out of
four human breast cancer cell lines85 and with daunorubicin and idarubicin in two
human AML cell lines.86 Cerivastatin potentiated cytotoxic effects of doxorubicin against
two human breast cancer cell lines.87 On the other hand, lovastatin has also been shown
to protect normal Chinese hamster ovary CHO-K1 cells from the cytotoxic effects of
doxorubicin.88
The mechanisms involved in stronger antitumor effects of doxorubicin plus statins
combination remain to be elucidated. One of the potential mechanisms relates to the receptor
for the insulin-like growth factor-1 (IGF-1R). Inhibition of the expression of IGF-1R in
tumor cells was found to increase their sensitivity to doxorubicin89 and statins have been
demonstrated to inhibit surface expression of this receptor90 by suppressing N-linked
glycosylation of IGF-1R and its translocation to the cell membrane.91–93 Statins have also
been shown to inhibit activation of nuclear factors kB (NF-kB) in tumor cells.82,94,95
Although inhibition of NF-kB was suggested to sensitize some tumor cells to doxorubicin-
induced apoptosis,96 there were also suggestions that doxorubicin itself induces activation of
NF-kB,82,97 which is essential for cytotoxic effects of doxorubicin.98,99 In one of the studies
simvastatin was proposed to increase doxorubicin cytotoxicity in human colon cancer cells as
a result of NF-kB activation.100 Relationship between doxorubicin sensitivity and NF-kB
activation may be cell-specific and may also depend on the level of NF-kB in tumor cells
preceding incubation with doxorubicin. Discussion on the effect of NF-kB activation on
tumor development and sensitivity of tumor cells to chemotherapy is further confounded by
the observations that although NF-kB displays tumor-promoting activities under some cir-
cumstances, it could also act as tumor suppressor.101 As statins inhibit proliferation of tumor
cells predominantly in G1 phase of the cell cycle26,27,29,45,102 and doxorubicin at low con-
centrations causes preferentially G2 arrest,103 they could probably supplement each other in
their inhibitory effects on the progression of tumor cells through the cell cycle.

Statins can also overcome resistance of tumor cells to doxorubicin. Multidrug resistance
(MDR) is caused by the overexpression of P-glycoprotein (PGP)104 or MDR-associated
proteins.105 Statins have been shown to interfere with the function of PGP by inhibiting
PGP-mediated transport.106,107 One of the mechanisms responsible for reversal of doxor-
ubicin resistance by statins may depend on the induction of nitric oxide (NO) synthase and
tyrosine nitration of either a PGP104 or an MRP-3 protein.105 MDR-resistant tumor cell lines
could happen to be more sensitive to lovastatin than doxorubicin-sensitive parental cells.108
However, in a prospective phase II study, high-dose simvastatin was not able to reverse
resistance to vincristine, adriamycin, and dexamethasone (VAL) chemotherapy in multiple
myeloma patients.109
The activated ras oncogenes in human cells confer resistance to doxorubicin and other
chemotherapeutics110–112 constituting a serious clinical problem as activating mutations of
ras genes are present in about 30% of all human cancers.113 The most significant signaling
cascades activated by RAS proteins include RAF/mitogen-activated extracellular signal-
regulated kinase kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) and the
phosphatidylinositol 3-kinase (PI-3K)/AKT pathways,114 both participating in doxorubicin
resistance in tumor cells,112,115 stimulating antiapoptotic events116,117 and expression of
PGP.116,118 Prenylation of RAS proteins seems to be essential for their function.119 By in-
hibiting formation of mevalonate-derived prenyl groups, statins can interfere with all RAS-
mediated pathways and RAS-associated doxorubicin resistance (Fig. 2).
The potential clinical significance of synergistic or additive antitumor activity of statins
and anthracyclines remains to be determined. However, significantly prolonged survival was
observed in patients with hepatocellular carcinoma treated with doxorubicin plus 5-fluor-
ouracil chemotherapy and pravastatin.73 In a phase 1 study, pravastatin was added to
conventional therapy including idarubicin and high-dose cytarabine in AML patients.120
Pravastatin was also shown to potentiate antitumor effects of farmorubicin-based che-
moembolization in patients with hepatocellular carcinoma.121
Although anthracyclines have been widely used in the treatment of both solid and he-
matological malignancies, anthracycline-induced cardiotoxicity remains a serious adverse
effect. Therefore, lovastatin-mediated attenuation of doxorubicin-associated cardiotoxicity78
in tumor-bearing mice and protection of endothelial cells from cytotoxic effect of doxor-
ubicin122 suggest additional advantages of using statins in combination with anthracyclines
of potential clinical relevance.
B. Platinum Compounds
Lovastatin has been shown to synergistically potentiate cytostatic/cytotoxic effects of cis-
platin in mouse melanoma cells (Table III) and to strengthen antitumor activity of cisplatin
in melanoma model in mice123 (Table II). Pre-treatment with lovastatin was also demon-
strated to augment pro-apoptotic effects of cisplatin in all four human colon carcinoma cell
lines tested124 and cerivastatin enhanced cisplatin-induced apoptosis in one out of two human
breast carcinoma cell lines tested.87 Combination of lovastatin and oxaliplatin potentiated
(at border-line significance) pro-apoptotic effects in one out of two human head and neck
squamous cell carcinomas (SCCs).125
The mechanism underlying the potentiated antitumor effects of combination therapy
with cisplatin and statins remains to be elucidated. As statins induce G1 arrest in pro-
liferating tumor cells26,27,29,45,102 and cisplatin seems to exert cytotoxicity preferentially in
G1-arrested cells126–128 this may be one of the possible mechanisms of the strengthened
antitumor activity. Statins are also known to inhibit activity of the ERK1/2 kinases129,130
and inhibition of these kinases results in enhanced sensitivity of tumor cells toward
Figure 2. Protein isoprenylation and post-prenylation reactions. Proteins such as RAS, RHO, and RAC undergo isoprenylation
reaction at cysteine residue (C) within the C-terminal CAAX sequence (where A is an aliphatic and X any amino acid). This is fol-
lowed by proteolytic removal of the AAX tripeptide by RAS-converting enzyme 1 (RCE1) and carboxymethylation by iso-
prenylcysteine carboxymethyltransferase (ICMT) in the endoplasmic reticulum. Subsequently, the proteins are palmitoylated in the
Golgi and transferred to the plasma membrane, to which they attach through their farnesyl or geranylgeranyl, and palmitoyl moi-
eties. FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
cisplatin.131–133 It cannot be excluded that in addition to potentiating therapeutic effects of

cisplatin statins could alleviate some of its toxic side effects. It has been demonstrated in the
experimental rat model that simvastatin was able to attenuate cisplatin-induced kidney and
liver damage.134
However, the potentiating effects of statins on cisplatin-mediated antitumor activity do
not seem to be universal. Lovastatin failed to strengthen significantly cytotoxic effects of
Table III. Antitumor Effects of Other Drugs Potentiated In Vitro by Statins
Tumor cells Chemotherapeutic Statin Type of effect in tumor cellsa References
124
Human SW480, HCT116, LoVo, and HT29 Cisplatin Lovastatin Apoptosis Potentiation
colon carcinoma
87
Human T4-2 breast carcinoma Cisplatin Cerivastatin Cytostatic/cytotoxic Synergisticb
83
Human p53-deficient H1299 NSCLC Cisplatin Atorvastatin Cytostatic Potentiation
123
Mouse MmB16 melanoma Cisplatin Lovastatin Cytostatic/cytotoxic Synergistic
125
Human SCC9 head and neck squamous Oxaliplatin Lovastatin Apoptosis Potentiationc
cell carcinoma
124
Human SW-480, HCT116, LoVo, and HT29 5-Fluorouracil Lovastatin Apoptosis Potentiation
colon carcinoma
135
Human H630, and R10 colorectal 5-Fluorouracil Cerivastatin Cytotoxic Potentiation
carcinoma
83
Human p53-deficient H1299 NSCLC 5-Fluorouracil Atorvastatin Cytotoxic Potentiation

82
Human KMB-5 myeloid leukemia 5-Fluorouracil Simvastatin Apoptosis Synergistic
137
Human K562 erythroleukemia and Paclitaxel Lovastatin Cytostatic/cytotoxic Synergistic
HL-60 AML
82
Human KMB-5 myeloid leukemia Paclitaxel Simvastatin Apoptosis Synergistic
125
Human SCC9 head and neck squamous Paclitaxel Lovastatin Apoptosis Potentiationc
cell carcinoma
83
Human p53-deficient H1299 NSCLC Etoposide Atorvastatin Cytostatic/cytotoxic Potentiationd
83
Human p53 wild-type A549 NSCLC Etoposide Atorvastatin Cytostatic Potentiatione
83
Human p53 wild-type HepG2 hepatoma Etoposide Pravastatin Cytostatic Potentiation
30
Human H-69 and H-510 NSCLC Etoposide Simvastatin Cytostatic Potentiation
141
Human K562 erythroleukemia Cytosine arabinoside Lovastatin Cytotoxic Synergistic
142
Human HL-60 and OCI/AML-2 AML Cytosine arabinoside Simvastatin Cytostatic Potentiation
86
Human AML-193 and KG-1 AML Cytosine arabinoside Fluvastatin Cytostatic Synergistic
84
Human primary AML Cytosine arabinoside Mevastatin Apoptosis Synergistic in 19%
of samples
84
Human NB4 AML Cytosine arabinoside Mevastatin Apoptosis Potentiation

143
Human MIAPaCa-2 pancreatic cancer Gemcitabine Fluvastatin Cytostatic Synergistic
K
124
Human SW-480, HCT-116, LoVo Sulindac Lovastatin Apoptosis Potentiation
colon carcinoma
109
Table III. Continued
110
K
147
Human HT-29 colon carcinoma Celecoxib Lovastatin Apoptosis Synergistic
144
Human PC-3, LNCaP, CWR22Rv1, and Du145 Celecoxib Atorvastatin Cytostatic Potentiationf
prostate cancer
145
Human HCT116 and HT29 colon Celecoxib Atorvastatin Cytostatic Synergistic
carcinoma
146
Murine colon-26 and CMT-96 colon MF-tricyclic Lovastatin Cytostatic/cytotoxic Synergisticg
carcinoma
JAKOBISIAK AND GOLAB
154
Human NCI-H929, RPMI-8226, LP-1, OPM-2, L-744,832 Lovastatin Cytostatic Synergistic
L363 and U266 multiple myeloma and purified GGTI-2147
primary multiple myeloma
155
Human NF90-8 and ST88-14 peripheral nerve FTI Lovastatin Cytostatic, apoptosis Potentiationh

sheath tumor
161
Human NCI-H929 multiple myeloma Zoledronate Simvastatin Apoptosis Synergistic
162
Human RPMI-8226, LP-1, OPM-2, Zoledronate Fluvastatin Cytostatic/cytotoxic Synergistic
NCI-H929 and U266 multiple myeloma
163
Human PANC-1 and Mia PaCa2 and murine Pamidronate Lovastatin Cytostatic/cytotoxic Synergistic
Panc02 pancreatic cancer cell lines,
human MDA-MB231 and
MDA-MB361 breast cancer
165
Human DBTRG-05MG glioblastoma and Troglitazone Lovastatin Cytostatic/cytotoxic Synergistici
CL1-0 lung cancer
166
Human MDA-MB231 breast cancer, Mia Ciglitazone Lovastatin Cytostatic/cytotoxic Synergistic
PaCa2 pancreatic cancer and murine
C-26 colon adenocarcinoma, Panc02 pancreatic
cancer and EMT6 breast cancer
170
Human Caco-2 and HCT-116 colorectal Butyrate Mevastatin Cytostatic Potentiation
carcinoma
171
Mouse colon-26 carcinoma Butyrate Mevastatin Cytostatic Potentiation
172
Mouse Lewis lung carcinoma Butyrate Lovastatin Cytostatic/cytotoxic Synergistic
173
Human A172 glioblastoma Phenylacetate Lovastatin Cytostatic Synergistic
174
Rat HTC-4 hepatoma Mitomycin C Lovastatin Cytostatic Potentiation
Human U937, HL-60 AML, Jurkat, Raji Lovastatin,
lymphoma, U266, MM.1S, MM.1R, 7-Hydroxy- Fluvastatin,
175
RPMI8226 myeloma and primary AML staurosporine Simvastatin Apoptosis Synergistic
Synergistic/
176
Human Huh-7 hepatocellular carcinoma Enzastaurin Lovastatin Cytostatic/cytotoxic potentiation
177
Human U87MG glioblastoma Gefitinib Lovastatin Cytostatic/cytotoxic Synergistic
Human SCC9 NSCLC, SIHA cervical
178
carcinoma and HCT116 colon cancer Gefitinib Lovastatin Cytostatic/cytotoxic Synergistic j
EGF-R tyrosine kinase

125
Human SCC9, SCC25 HNSCC inhibitor AG1478 Lovastatin Apoptosis Potentiationk
179
Human primary myeloma cell cultures Thalidomide Lovastatin Apoptosis Potentiation
Human multiple myeloma (MM) XG1
and OPM-2 and primary myeloma Lenalidomide
180
cell cultures (thalidomide analogue) Simvastatin Cytostatic/cytotoxic Potentiation
181
Human glioma Carmustine Simvastatin Cytostatic Synergistic
182
Rat C6 astrocytoma Carmustine Simvastatin Cytostatic Synergistic
Synergistic for
FGIN-1-27
Human Huh-7 and HepG2 hepatocellular Peripheral benzodiazepine Fluvastatin, and additive for PK
184
carcinoma receptor ligands Pravastatin Cytostatic 11195 ligands
183
Human KMS-12PE myeloma Dexamethasone Simvastatin Cytostatic Potentiation
Synergistic in two out
Human MCF7/wt, MCF/adr, BT474, SK-BR-3 of four cell
85
breast carcinoma Sirolimus (rapamycin) Fluvastatin Cytotoxic lines studied

86
Human AML-193 and KG-1 AML Sirolimus (rapamycin) Fluvastatin Cytotoxic Synergistic
K
86
Human AML-193 and KG-1 AML Everolimus Fluvastatin Cytotoxic Synergistic
111
112
K
186
Human HT29 colon adenocarcinoma Photofrin II in Lovastatin Cytotoxic Potentiation
photodynamic
therapy
187
Human Raji and Daudi non-Hodgkin’s Saquinavir Lovastatin Cytostatic/cytotoxic Potentiation
lymphoma
221
Human HepG2 hepatocellular cancer Cetuximab Fluvastatin Cytostatic/cytotoxic Potentiation
85
Human MCF7 and SK-BR-3 breast Trastuzumab Fluvastatin Apoptosis Synergistic
cancer
191
Human H1299 and H460 lung cancer Green tea polyphenols Atorvastatin Cytostatic Synergistic
Abbreviations: AML, acute myeloid leukemia; EGF-R, epidermal growth factor receptor;FTI, farnesyl transferase inhibitor; GGTI, geranylgeranyl transferase inhibitors; NSCC,
head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

a
When interaction was not determined as being synergistic, the term ‘‘potentiation’’ was us used.
b
Potentiation was not observed in human breast carcinoma MDA-MB-231 cells.
c
At border-line of significance.
d
Potentiation observed at 0.5 mM etoposide concentration but not at higher concentration (41 mM).
e
Potentiation observed at etoposide concentrations (0.1--1 mM and 1 mM) but not at higher concentration (410 mM).
f
In PC-3 cells potentiation of apoptosis was also observed.
g
Potentiation was not observed in murine melanoma B16F10 and human bladder carcinomaT24 cells.
h
No detectable toxicity of the combination was observed in normal rat Schwann cells.
i
No synergism was observed for the combination of lovastatin with neither ciglitazone nor rosiglitazone.
j
Potentiation was also observed for eight of eight squamous cell carcinomas, four of four non-small cell lung carcinoma, and four of four colon carcinoma cell lines tested.
k
Potentiation was not observed in human MCF-7 breast carcinoma cell line.
cisplatin in human head and neck SCC9 and SCC25 cell lines and in human breast carcinoma
MCF-7 cell line.125
C. 5-fluorouracil
Statins have also been demonstrated to strengthen cytotoxicity of 5-fluorouracil in tumor
cells (Table III).82,83,124,135 Cytotoxic effects of 5-fluorouracil in human colon cancer cells
were potentiated by both lovastatin124 and cerivastatin.135 Cerivastatin enhanced 5-fluor-
ouracil cytotoxicity both in chemoresistant and in chemosensitive tumor cells.135 Atorvas-
tatin potentiated the antiproliferative effects of 5-fluorouracil in human non-small cell lung
cancer cells83 and simvastatin synergistically enhanced cytotoxic effects of 5-fluorouracil in
human myeloid leukemia cells.82 One of the potential mechanisms responsible for these
strengthened antitumor effects could be inhibition by statins of NF-kB activation sensitizing
tumor cells to 5-fluorouracil.82 Clinical significance of these observations remains to be
determined. However, it is worth mentioning that in a randomized clinical trial survival of
patients with hepatocellular carcinoma was significantly prolonged, following standard
therapy with doxorubicin plus 5-fluorouracil when given in combination with pravastatin
compared with standard therapy alone.73 Unfortunately, it could not be concluded whether
therapeutic effects of this combination treatment depended on the beneficial interaction of
pravastatin with doxorubicin, with 5-fluorouracil or with both. However, liver function
deteriorated more rapidly in patients treated with standard therapy alone suggesting that
pravastatin not only did improve the effectiveness of chemotherapy in tumor patients but
also exerted some protective effects on hepatocytes. In another recent multicenter phase II
clinical trial, 5-fluorouracil, irinotecan, and leucovorin used in combination with simvastatin
as first-line chemotherapy in metastatic colorectal patients demonstrated promising anti-
tumor effects with 46.9% overall response rate.136
On the other hand, in human head and neck SCC9 and SCC25 cell lines and in human
breast carcinoma MCF-7 cell line, lovastatin did not potentiate cytotoxic effects of
5-fluorouracil.125
D. Paclitaxel
In human leukemic cells cytotoxic activity of paclitaxel has been potentiated synergistically
by lovastatin137 and simvastatin.82 Lovastatin has also strengthened cytotoxic effects of
paclitaxel in human head and neck SCC cells.125 Several mechanisms could be proposed to
account for this synergistic interaction. Through the inhibition of NF-kB, activation statins
could sensitize leukemic cells to paclitaxel, analogously to sensitization to doxorubicin and
5-flurorouracil.82 It has also been suggested that lovastatin could enhance paclitaxel-induced
G2/M arrest in leukemic cells.137 As lovastatin preferentially arrests tumor and normal
cells in G1 phase of the cell cycle26,27,29,45,102 but to some extend also in G2/M phase26,138
and paclitaxel is being reported to cause G2/M arrest137,139 synergistic interaction of these
two drugs in tumor cells could result from simultaneous inhibition of two different phases of
the cell cycle. On the other hand, lovastatin has not been shown to potentiate cytotoxic
effects of paclitaxel in human SCC25 head and neck SCCs and in human MCF-7 breast
carcinoma cell line, and only border-line significance of potentiation was achieved in
SCC9 cells.125
E. Etoposide
Atorvastatin and pravastatin augmented antiproliferative effects of etoposide in human non-
small cell carcinoma and hepatoma cells83 and simvastatin did so in human small cell
carcinoma cells.30 Potentiating effect of atorvastatin was observed in both, p53 wild-type and
p53-deficient tumors cells.83 It has been suggested that statin-induced mTOR-dependent inhibition
of AKT activation was responsible for sensitization of tumor cells to etoposide.83 This conclusion
is supported by the observations showing potentiation of antitumor effects of etoposide140 or
attenuation of resistance to etoposide115 by inhibitors of PI-3K/AKT signaling pathway.
F. Cytosine Arabinoside
Statins have been found to potentiate antileukemic activity of cytosine arabinoside.84,86,141,142
It is particularly interesting that this effect has been observed not only in leukemic cell
lines84,86,141,142 but also in some primary AML cells isolated from the patients.84 The inter-
action between cytosine arabinoside and mevastatin was described in these primary AML cells
as greater than additive84 and as synergistic between cytosine arabinoside and fluvastatin86 in
three human AML cell lines. It has been proposed that downregulation of the ERK1/2 kinases
by statins may be one of the mechanisms participating in potentiation of antileukemic effects of
this chemotherapeutic.141 Antiproliferative activity of gemcitabine (cytosine arabinoside ana-
log) was potentiated synergistically in human pancreatic cancer cells by fluvastatin.143 Again,
statin-induced suppression of ERK kinases was suggested as one of the possible mechanisms of
the observed strengthened antitumor effects.143
G. Cyclooxygenase Inhibitors
Combination of statins with cyclooxygenase (COX) inhibitors also resulted in potentiated
cytostatic144–146 and pro-apoptotic3,146,147 effects in tumor cells (Table III). Potentiation was
observed when statins were combined with both selective COX-2 inhibitors144–147 and non-
selective COX-1 and COX-2 inhibitors.148 In some of these studies, synergistic interactions of
statins and these inhibitors were observed.3,145,146 The mechanism responsible for potentiated
antitumor effects has not been elucidated but decrease in geranylgeranylated RHOA and
RHOC membrane-bound proteins,145,148 decrease in activated ERK1/2 kinases,144 AKT
kinase145 and NF-kB,144 and synergistic upregulation of cyclin-dependent kinase inhibitors
p21 and p27145 all may participate in these effects. Combined treatment of human colon
carcinoma cells with either lovastatin or atorvastatin and celecoxib resulted in cell cycle arrest
in G0/G1 and apoptosis after prolonged exposure, which were much stronger than those
observed with either agent alone.145,147 Combination of atorvastatin and celecoxib also
produced potentiated antitumor effects in immunodeficient mice injected with human
prostate cancer PC-3 cells.144 It is worth mentioning that lovastatin combined with su-
lindac148 and atorvastatin used in combination with celecoxib3,149 demonstrated potentiated
chemopreventive effects in experimental models of colon carcinogenesis.
H. Drugs that Target Mevalonate Pathway

Farnesyltransferase inhibitors (FTI) have been developed to specifically target RAS proteins,
the products of the most frequently mutated oncogenes in human cancers. However, despite
promising pre-clinical results and good safety profiles in initial clinical trials, their antitumor
efficacy in humans turned out to be limited, especially in the treatment of solid tumors.150,151
A likely explanation for poor FTIs’ activity in clinical trials is that KRAS and NRAS, which
are more frequently mutated than HRAS, can undergo an alternative prenylation by ger-
anylgeranyl transferase I (GGT) in FTI-treated cells.151 Therefore, the idea of using com-
binations of prenylation inhibitors including FTI together with GGT inhibitors (GGTI) or
statins has been suggested to avoid cross-geranylgeranylation of these proteins.152 Although
statins inhibit the formation of both FPP and GGPP, the majority of studies indicate that
most of the antitumor effects of these drugs result from preferential inhibition of ger-
anylgeranylation.153 In contrast to GGTI, statins are very well tolerated and their combi-
nation with FTI might provide a wider therapeutic window. Indeed, in vitro studies revealed
that lovastatin in combination with various FTIs and GGTI is superior to either agent used
alone in inducing antiproliferative, anti-invasive, and cytotoxic effects against multiple
myeloma cells.154 Similarly, combination of lovastatin and two novel FTIs has recently been
shown to reduce proliferation and induce apoptosis of peripheral nerve sheath tumor cells,
having no detectable toxicity toward normal rat Schwann cells.155
Bisphosphonates (BPs) such as aledronate, pamidronate, or zoledronic acid are synthetic
analogs of pyrophosphoric acid that are currently used in the clinic for a variety of conditions
associated with increased bone resorption, such as post-menopausal osteoporosis, corticos-
teroid-induced bone loss, and Paget’s disease. These drugs are also used in patients with
malignant hypercalcemia associated with various malignancies and for treatment of bone
metastases from solid tumors.156 The mechanisms of BPs action include direct suppressing
effects on bone osteoclast precursors. Recent studies revealed that nitrogen-containing BPs
(N-BPs) can also exert direct cytostatic/cytotoxic effects toward tumor cells.157 N-BPs inhibit
proliferation and induce apoptosis of a number of human tumor cell lines in vitro, inhibit the
ability of tumor cells to adhere to mineralized or unmineralized matrices, and to invade
extracellular matrix. In vivo animal studies revealed their antitumor and antimetastatic ef-
fects that might result from both direct action on tumor cells and inhibition of tumor
angiogenesis.157 At the molecular level N-BPs inhibit farnesyl diphosphate synthase, an
enzyme of the mevalonate pathway.158 Increasing number of observations indicate that BPs
exert synergistic antitumor activity when used in combinations with cytotoxic drugs, targeted
molecular and biological therapies as well as radiotherapy. Zoledronic acid and pamidronate
have been shown to enhance growth inhibition and apoptosis when used together with
R115777, a farnesyl transferase inhibitor.159 Aledronate together with R115777 decreased the
number of lung metastases in mice, but this combination was ineffective in terms of influence
on primary tumor growth.160 As statins indirectly inhibit both farnesylation and ger-
anylgeranylation of cellular proteins, their combination with BPs might provide additional
antitumor effects. Indeed, simvastatin effectively potentiated antimyeloma activity of zole-
dronic acid, and reversed cell adhesion-mediated resistance of tumor cells to melphalan and
bortezomib.161 Similarly, fluvastatin, but not SCH66336 a farnesyl transferase inhibitor,
potentiated antimyeloma activity of zoledronic acid.162 Synergistic potentiation of cytostatic
and cytotoxic effects against both human and murine solid tumor cell lines was also observed
using the combinations of pamidronate with lovastatin, mevastatin, atorvastatin, simvasta-
tin, or cerivastatin.163 Combination of lovastatin with pamidronate was also more effective
than single agents in inhibiting adhesion to extracellular matrix protein and invasion through
matrigel even at 200–250 nM concentrations of lovastatin. The growth inhibiting influence of
the lovastatin/pamidronate combination was reversed more effectively by geranylgeranyl
pyrophosphate (GGPP) than farnesyl pyrophosphate (FPP), and additionally GGTI-298 was
superior to FTI-277 in potentiating cytostatic/cytotoxic effects of pamidronate against tumor
cells.163 Although neither antitumor effects of lovastatin nor pamidronate administered alone
was observed, there was a significant retardation of tumor growth and prolongation of mice
survival in animals treated with both agents simultaneously.163
3. COMBINATIONS WITH OTHER DRUGS
Statins have been reported to indirectly activate peroxisome proliferator-actiavated receptor

g (PPAR-g).164 Despite targeting the common transcription factor, combination of lovastatin
and thiazolidinediones (PPAR-g agonists) resulted in potentiated cytostatic/cytotoxic effects

against various human and murine tumor cells.165,166 In both reports, the interaction between
statin and PPAR-g agonists was strongly synergistic, and observed at lovastatin concentra-
tions as low as 125 nM.166 Combination of these drugs has not been studied in tumor patients
yet, but was already evaluated in clinical trials, being superior to every single drug in terms of
improving overall cardiovascular risk profile, reducing cholesterol levels and producing anti-
inflammatory effects.167–169
Antitumor activity of butyrate, which is a natural short-chain fatty acid produced by
anaerobic fermentation of dietary fibers in the human colon, has been potentiated by statins
against human colorectal carcinoma cells170 and murine colon171 and lung carcinoma cells.172
These strengthened antitumor effects have been demonstrated both in vitro170–172 and in
murine tumor model using butyrate prodrug tributyrin.172 Lovastatin has also augmented
cytostatic activity of butyrate derivative phenylacetate in human glioblastoma cells.173 In two
of these studies the interaction of drugs was found to be synergistic.172,173 The mechanisms
responsible for potentiated antitumor effects in these combination therapies have not been
elucidated but inhibition of G1 phase of the cell cycle by both butyrate and statins but using
different mechanisms has been proposed.170
Antitumor effects against tumor cells of many other drugs have also been potentiated by
their combined application with statins including mitomycin C,174 7-hydroxystaurosporine,175
enzastaurin,176 epidermal growth factor inhibitors gefitinib177,178 and AG1478,125 thalido-
mide,179 lenalidomide (thalidomide anologue),180 and carmustine181,182 (Table III). It has been
suggested that synergistic interaction between 7-hydroxystaurosporine and statins in tumor
cells could be caused by a shift from the survival signal transduction pathways (RAF/MEK/
ERK and PI3K/AKT) toward the stress-related c-Jun N-terminal protein kinase (JNK)
pathway.175 Potentiated antitumor effects of combined application of the epidermal growth
factor receptor (EGF-R) inhibitor and lovastatin may result from interference of both drugs
with the function of EGF-R at two separate levels with one directly inhibiting its tyrosine
kinase activity and the other inhibiting, through dolichol depletion, its glycosylation which is
essential for its proper function.125
Strengthened cytostatic effects have been shown when human myeloma cells were treated
with combination of dexamethasone and simvastatin.183 Synergistic interactions have been
observed in tumor cells between fluvastatin and inhibitors of mammalian target of rapamycin
(m-TOR). Fluvastatin demonstrated synergistic cytotoxic effects in two out of four human
breast carcinoma cell lines when combined with sirolimus (rapamycin)85 and in two human
AML lines when combined with both sirolimus and everolimus.86 The combination of flu-
vastatin or pravastatin with ligands of the peripheral benzodiazepine receptors synergistically
or additively inhibited proliferation of human hepatocellular carcinoma cells184 and synergy
between lovastatin and amphibian oocyte ribonuclease in inducing cytostatic and cytotoxic
effects has also been observed in human lung and pancreatic carcinoma cells.185
Incubation of tumor cells with lovastatin has been shown to increase low-density lipo-
proteins (LDL) uptake. This property was exploited to increase tumor uptake of photofrin, a
hydrophobic photosensitizer used in photodynamic therapy (PDT) that selectively binds to
LDLs. Pre-incubation of tumor cells with lovastatin increased photofrin uptake and sensi-
tized human colon adenocarcinoma cells to cytotoxic effects of PDT.186
Lovastatin has also been shown to potentiate cytostatic/cytotoxic effects of antiretroviral
protease inhibitor saquinavir against human non-Hodgkin’s lymphoma cells.187 This
combination might be particularly attractive for human immunodeficiency-infected patients
as the use of protease inhibitors has been associated with the development of dyslipidemia,
coronary artery disease, and increased risk of myocardial infarction.188 Statins could coin-
cidentally improve antitumor effectiveness of saquinavir or other drugs and specifically
ameliorate protease inhibitor-induced alterations in lipid metabolism and cardiovascular

complications. However, combining statins with protease inhibitors should be done with
caution as both the groups of drugs undergo CYP3A4-mediated metabolism, and the in-
creased exposure to statins has been reported as a result of their co-administration with
ritonavir and saquinavir.189 Moreover, a small exploratory clinical trial revealed that con-
comitant administration of statins and protease inhibitors significantly reduces T lymphocyte
renewal.190 Although this observation confirms that the interactions between these drugs are
clinically feasible, it also reveals potential risks associated with the concomitant adminis-
tration of these drugs in combination.
In an interesting study, combination of atorvastatin and standardized preparation of green
tea polyphenols, known mainly for their anticarcinogenic effects, has been examined.191
Interaction of atorvastatin with this preparation resulted in synergistic antitumor cytostatic
effects in human tumor lung cancer H1299 and H460 cells in vitro and potentiated inhibition of
lung tumorigenesis induced in mice by the administration of chemical carcinogen.191
Simvastatin has been shown to overcome cell-adhesion-mediated drug resistance to
melphalan in human myeloma cells by the inhibition of RHO kinases.192 However, when
patients with multiple myeloma undergoing hematopoietic stem cell transplantation after
conditioning with high-dose melphalan were divided into those taking statins and those
without the history of statin use, no improvement of progression-free survival or overall
survival has been observed.193
On the other hand, combination of statins with actinomycin D and cycloheximide,
resulted in diminished cytotoxic effects in three human head and neck SCC cell lines.125
4. COMBINATION WITH VITAMINS AND THEIR ANALOGS
The combined application of statins with certain vitamins and their analogs has also resulted
in strengthened antitumor effects (Table IV). Combination of 13-cis-retinoic acid with me-
vastatin produced potentiated antiproliferative effects in mouse neuroblastoma cells.194
Combination of all-trans-retinoic acid (ATRA) with simvastatin resulted in enhanced cyto-
static effects against human myeloma cells183 and strengthened differentiation of human
acute promyelocytic leukemia cells.195 Lovastatin has also been shown to partially restore
ATRA sensitivity of human AML cells.196 Treatment of mouse neuroblastoma cells with
both a-tocopheryl succinate, vitamin E analog, and mevastatin produced potentiated anti-
proliferative effects.194 Furthermore, g-tocotrienol, vitamin E isomer containing isoprenoid
moiety, produced synergistic antiproliferative activity against murine mammary carcinoma
cells when combined with either simvastatin, mevastatin, or lovastatin197 and synergistic
antiproliferative activity against mouse melanoma cells when combined with lovastatin.198
Synergistic interaction was also observed when g-tocotrienol and lovastatin were used in
combination in melanoma-bearing mice.198
5. COMBINATION WITH RADIOTHERAPY
Lovastatin has been shown to increase the sensitivity of human tumor cells to cytotoxic effects
of ionizing radiation.199,200 As activated RAS confers radioresistance on tumor cells199,201
statins could increase radiosensitivity in tumor cells bearing ras mutations by interference with
the function of RAS oncoproteins. On the other hand, lovastatin arrests tumor cells specifically
at the G1 phase of the cell cycle,26,27,29,45,102 which seems to make them particularly vulnerable
to the effects of ionizing radiation.202 As G2 arrest is characteristic for irradiated cells,203,204 the
118
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Table IV. Antitumor Effects of Vitamins and Their Analogs Potentiated In Vitro by Statins
Interaction of
vitamin and statin
Tumor cells Cytokine Statin Type of effect in tumor cellsa References
183

Human KMS-12PE myeloma ATRA Simvastatin Cytostatic Potentiation
195
Human NB4AML ATRA Fluvastatin, atorvastatin Differentiation Potentiation
194
Mouse NBP2 neuroblastoma 13-cis-Retinoic acid Mevastatin Cytostatic Potentiation or synergisticb
194
Mouse NBP2 neuroblastoma a-Tocopherol succinate Mevastatin Cytostatic Synergistic
197
Mouse neoplastic 1SA g-Tocotrienol Simvastatin, lovastatin, Cytostatic Potentiation
mammary carcinoma mevastatin, or pravastatin
198
Mouse B16F10 melanoma g-Tocotrienol Lovastatin Cytostatic Synergistic
Abbreviations: ATRA, all-trans-Rerinoic acid.
a
b
An additive effect at concentrations of 8.3 and 16.6 mM and synergistic effects at concentrations of 33.3 and 49.9 mM of 13-cis-retinoic acid.
more potent antitumor effects of treatment combining ionizing radiation with statins could
also result from blocking cell cycle progression in tumor cells at two different phases of the cell
cycle. An additional advantage of using this combination therapy could be the ability of statins
to diminish radiation-induced toxicity.205 Pravastatin has been shown to improve endothelial
cell function following radiation, diminishing the risk of atherosclerosis development206 and to
protect rats from delayed radiation-induced enteropathy205,207 without interfering with anti-
tumor effects of radiotherapy.207
However, it has to be stressed that statin-induced enhancement of tumor cell radio-
sensitivity has been questioned by some observations. In one study, lovastatin was not able to
improve the antitumor effects of radiation in vitro or in tumor-bearing mice.208
6. COMBINATION WITH IMMUNOTHERAPY
A. Cytokines
Statins have potentiated antitumor effects of tumor necrosis factor (TNF) both in vitro209,210
(Table V) and in experimental tumor models65,211 (Table II). Simvastatin augmented cyto-
toxic activity of TNF in human myeloid cells and lovastatin synergistically strengthened
cytostatic activity of TNF in mouse melanoma cells in vitro210 and its therapeutic effects in
melanoma-bearing mice.211 Several explanations of the potential mechanism of these inter-
actions have been proposed. The fate of cells exposed to TNF is determined by the inter-
action of signals mediated by different effector molecules including caspases, inhibitors of
NF-kB (IkBs), also called inhibitory kB proteins, IkB kinase (IKK) complex consisting of
one a, one b, and two g subunits, and JNK. Activation of caspases is required for apoptosis,
whereas IKK activation inhibits apoptosis through NF-kB as a result of ubiquitin-mediated
degradation of its inhibitor, IkBa.212 Antiapoptotic signals of NF-kB result from down-
regulation of JNK.213 As statins inhibit activation of NF-kB82,94,95 and are even suggested to
induce its inactivation,60 synergistic interaction of TNF and statins may result from inter-
ference of statins with mechanisms protecting tumors cells from TNF-induced apoptosis.209
It has already been shown that inhibition of NF-kB increases susceptibility to TNF-induced
cell death.214 As statins have been shown to arrest tumor and normal cells in the G1 phase of
the cell cycle26,27,29,45,102 and G0/G1 arrested cells seem to be more sensitive to TNF-medi-
ated killing,215 this mechanism could also participate in synergy between statins and TNF in
tumor cells. Another potential mechanism of this synergy could be stimulation by statins of
the expression of TNF type 1 receptor.216
Inhibition of NF-kB activation and arrest of tumor cells in G1 phase by statins could
also be responsible for their ability to strengthen cytotoxic effects of TNF-related apoptosis-
inducing ligand (TRAIL), another cytokine belonging to TNF family in human colon car-
cinoma and glioblastoma cells217,218 (Table V).
Simvastatin synergistically augmented antiproliferative effects of interferon-b in human
glioma cells181 and lovastatin augmented these effects of interferon-a in human myeloid
cells219 (Table V). Simvastatin in these experiments was used at concentrations that are
achieved in patients treated for their cardiovascular problems.181 According to unpublished
data cited in the last article,181 synergistic cytostatic effects with of interferon-b was also
demonstrated with pravastatin and fluvastatin.
B. Monoclonal Antibodies
Antibodies can exert antitumor effects via multiple mechanisms including activation of an-
tibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC),
120
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Table V. Antitumor Effects of Cytokines Potentiated In Vitro by Statins
Interaction of cytokine and

Tumor cells Cytokine Statin Type of effect statin in tumor cellsa References
209
Human KBM-5 myeloid leukemia TNF Simvastatin Apoptosis Potentiation
210
Mouse MmB16 melanoma TNF Lovastatin Cytostatic Synergistic
217
Human SW480 colon carcinoma TRAIL Simvastatin Apoptosis Potentiation

Lovastatin
218
Human A172, M059J, M069K TRAIL Lovastatin Apoptosis Synergistic
glioblastoma
181
Human glioma Interferon-b Simvastatin Cytostatic Synergistic
219
Human K562 CML Interferon-a Lovastatin Cytostatic Synergistic
Abbreviations: CML, chronic myeloid leukemia; TNF, tumor necrosis factor; TRAIL,TNF-related apoptosis inducing ligand.
a
direct binding and inhibition of receptors for growth factors, induction of apoptosis by
activation of death receptors, or neutralization of growth and/or angiogenic factors.220
Statins can modulate antitumor effects of mAbs in various ways. For example, fluvastatin
was demonstrated to potentiate antiproliferative effects of cetuximab, an mAb-targeting
EGF-R, against hepatocarcinoma cells.221 The detailed mechanism of this interaction was
not studied in this report. However, targeting mevalonate pathway has been shown to inhibit
the function of EGFR and the combination of lovastatin and gefitinib, a small-molecule
inhibitor of EGFR kinase activity, showed cooperative cytotoxicity in squamous cell, lung
and colon cancer cell lines178 as well as in glioblastoma.177 Intriguingly, atorvastatin slows
the progression of pathologic cardiac remodeling induced by pressure overload in mice by
inhibiting EGFR activity.222 This observation might be of great clinical importance, con-
sidering an increasing number of observations indicating cardiotoxicity of anticancer ther-
apeutics. For example, the use of trastuzumab, an mAb against ERBB2 (EGFR2, HER2)
approved for the treatment of breast and ovarian carcinomas, is associated with a transient
and reversible cardiotoxicity, which can pose more significant problems when combined with
anthracyclines, such as doxorubicin and epirubicin. Addition of statins to such combinations
can not only limit cardiotoxicity, but coincidentally might additionally potentiate their an-
titumor effects. In pre-clinical studies, statins were shown to potentiate antitumor effects of
doxorubicin and to attenuate its cardiotoxicity (see above) and were also reported to sy-
nergistically increase cytotoxic effects of trastuzumab.85
Unexpectedly, statins almost completely impaired rituximab-mediated CDC and sig-
nificantly inhibited ADCC against human B-cell lymphoma cells.223 CD20, a rituximab
target antigen, is an integral membrane protein with tetraspanning topology. The correct
alignment of this molecule in the plasma membrane is dependent on the cholesterol content
in the latter. Statins and other cholesterol-depleting agents induced conformational shifts
within CD20 thereby affecting binding of anti-CD20 mAbs. Overall, statins were shown to
interfere with both detection of CD20 and antilymphoma activity of rituximab. A small
exploratory clinical trial in five healthy volunteers confirmed that short-term atorvastatin
treatment is associated with decreased binding of anti-CD20 mAbs to the surface of normal
B cells.223 These studies might have significant clinical implications as impaired binding of
mAbs to conformational epitopes of CD20 elicited by statins could delay diagnosis, postpone
effective treatment or impair antilymphoma activity of rituximab. However, a preliminary
clinical analysis did not show inferior clinical outcome of rituximab treatment in lymphoma
patients taking statins.224
C. Biological Response Modifiers

Bacille Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium tuberculosis. BCG
has been used as a vaccine against tuberculosis, as an adjuvant, or as a biological response
modifier. Intravesical BCG immunotherapy is an effective adjuvant for the management of
superficial bladder cancer.225 The most important mechanism of antitumor effects of BCG in
immunotherapy of superficial bladder cancer is activation of non-specific immunity with
local release of various cytokines.226 In a retrospective study, the use of statins was shown to
increase the risk of tumor progression in patients treated with BCG.227 As statins have
anti-inflammatory and immunomodulatory activities,4,5,228–231 they could interfere with
BCG therapeutic activity. However, two larger retrospective studies did not show any
significant association between statin use and efficacy of BCG treatment for bladder
cancer.232,233
7. COMBINATION WITH GENE THERAPY
It has been demonstrated that lovastatin could stimulate replication of oncolytic adenovirus
dl1520 (Onyx-015) and enhance its therapeutic effects against human thyroid carcinoma cells
both in vitro and in nude mice.234 Although this observation suggests that statins could be
used to increase antitumor activity of oncolytic viruses, it has to be kept in mind that statins
have also been shown to exert antiviral activity.235,236
8. CONCLUSION
Statins have found application in the effective management of hypercholesterolemia and are
among the most frequently used drugs worldwide. They also exert pleiotropic effects on
various cellular signaling pathways and cellular functions, and have shown antitumor activity
on tumor cells in vitro and in tumor-bearing animals. However, their therapeutic efficacy has
not been demonstrated in clinical tirals. Statins have also been shown to interact in various
ways with antitumor therapeutic modalities enhancing or in rare cases diminishing
their effectiveness. They could also attenuate toxic side effects of some chemotherapeutics.
Oncologists should be aware of these findings before choosing treatment modalities in tumor
patients taking statins for their cardiovascular problems. Future studies should concentrate
on those combinations in which statins significantly potentiate antitumor effects or diminish
toxicity of other treatment modalities in experimental tumor models to decide whether the
evidence of these results is strong enough to justify initiation of clinical trials. Examination of
the influence of statins on the effectiveness of novel antitumor drugs should also proceed.
ACKNOWLEDGMENTS
This work was partly supported by a grant N N405 302836 from Ministry of Science and
Higher Education in Poland and 1M19/N from the Medical University of Warsaw. The
sponsor had no role in the design of the study, the collection of the data, the analysis and
interpretation of the data, the decision to submit the manuscript for publication, or the
writing of the manuscript. The authors thank Joanna Ciecierska for critical reading of the
manuscript.
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Marek Jakobisiak was born in Warsaw in 1944 and studied medicine at the Medical University
of Warsaw. He obtained his M.D. degree in 1968, and his Ph.D. degree in 1972. The main area
of his scientific interst is experimental tumor therapy.
Jakub Golab was born in Warsaw in 1972. He obtained his M.D. degree in the Medical
University of Warsaw in 1998, and his Ph.D. degree in 1999. He works in the field of experi-
mental tumor therapy.

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Statins Can Modulate E¡ectiveness

Marek Jakobisiak and Jakub Golab

Published online 15 June 2009 in Wiley InterScience (www.interscience.wiley.com).

Key words: statins; chemotherapy; combination therapy; tumor

Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors that have

Medicinal Research Reviews, Vol. 30, No.1,102--135, 2010

2. COMBINATION WITH CHEMOTHERAPY

Chemotherapy is currently a mainstay of cancer therapy being either a primary cancer

Medicinal Research Reviews DOI 10.1002/med

Table II. Antitumor Effects of Various Therapeutic Modalities Potentiated by Statins in

Tumor Animal Therapy Statin References

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cisplatin.131–133 It cannot be excluded that in addition to potentiating therapeutic effects of

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Human NB4 AML Cytosine arabinoside Mevastatin Apoptosis Potentiation

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breast carcinoma Sirolimus (rapamycin) Fluvastatin Cytotoxic lines studied

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H. Drugs that Target Mevalonate Pathway

3. COMBINATIONS WITH OTHER DRUGS

Statins have been reported to indirectly activate peroxisome proliferator-actiavated receptor

and thiazolidinediones (PPAR-g agonists) resulted in potentiated cytostatic/cytotoxic effects

ameliorate protease inhibitor-induced alterations in lipid metabolism and cardiovascular

4. COMBINATION WITH VITAMINS AND THEIR ANALOGS

5. COMBINATION WITH RADIOTHERAPY

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6. COMBINATION WITH IMMUNOTHERAPY

Table V. Antitumor Effects of Cytokines Potentiated In Vitro by Statins

Interaction of cytokine and

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C. Biological Response Modifiers

7. COMBINATION WITH GENE THERAPY

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46. Herrero-Martin G, Lopez-Rivas A. Statins activate a mitochondria-operated pathway of

Medicinal Research Reviews DOI 10.1002/med

Medicinal Research Reviews DOI 10.1002/med

80. Feleszko W, Mlynarczuk I, Olszewska D, Jalili A, Grzela T, Lasek W, Hoser G, Korczak-

Medicinal Research Reviews DOI 10.1002/med

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leucovorin (FOLFIRI) as ﬁrst-line chemotherapy in metastatic colorectal patients: A multicenter

Medicinal Research Reviews DOI 10.1002/med

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172. Giermasz A, Makowski M, Kozlowska E, Nowis D, Maj M, Jalili A, Feleszko W, Wojcik C,

Medicinal Research Reviews DOI 10.1002/med

Medicinal Research Reviews DOI 10.1002/med

207. Haydont V, Gilliot O, Rivera S, Bourgier C, Francois A, Aigueperse J, Bourhis J, Vozenin-

Medicinal Research Reviews DOI 10.1002/med

Medicinal Research Reviews DOI 10.1002/med

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