2.1 Lipid Metabolism
Ovarian cancer is unique in abdominal implantation, a way of metastasis
compared with other epithelial malignancies, and the most common site of
metastasis is the omentum rich in fat. Omental adipocytes can secrete
adipokines to promote the selective orientation of cancer
cells[14]. Then, ECO cells interact with and
convert them into “cancer-associated adipocytes”[15], absorbing them to meet their demands for
energy. Mukherjee A et al.[15] report that
adipocytes can support requirements of ovarian cancer cells through the
reprogramming of glucose metabolism. In addition, cholesterol levels in
tumor cells were elevated compared to normal cells, and OC cells rely
more on uptake of exogenous lipids and
cholesterol[16].
De Wolf et al. found the up-regulation of HMGCR in ECO, compared with
normal ovarian epithelial
cells[17].
Interestingly, in platinum-resistant ovarian cancer cells,
HUANG X Y, et al. discover the
up-regulation of low-density lipoprotein receptor (LDLR) expression and
down-regulation of HMGCR expression[18]. The
factors inscribed into changes in the two drug targets is necessary to
be further studied. In addition, high cholesterol levels in tumor cells
is associated with platinum
resistance in ovarian cancer[19], possibly due to
preventing the entrence of platinum by reduction of the permeability and
fluidity of the cell membranes of cancer cells.
These studies suggest that lipid metabolism plays an important role in
the metastasis and drug resistance of ovarian cancer, and statins has
great potential in anti-ovarian cancer because it inhibits HMGCR in the
mevalonate
pathway
(MVAP) to reduce the production of cholesterol.
While Criscuolo,D.et al. declared
that statins in OC cells would induce platinum resistance by stimulating
exogenous cholesterol to increase intake due to
inhibition of
endogenous
cholesterol synthesis in the MVAP,
the conclution exists some paradox
theoretically[19].
Because it was based on the study of
HUANG X Y, et al. [18] about the up-regulation of
low-density lipoprotein receptor
(LDLR) expression and
down-regulation of HMGCR expression in platinum-resistant ovarian cancer
cell, which merely indicated that platinum-resistant cells have
increased uptake intensity of exogenous cholesterol. If statins would
increase intracellular cholesterol by activating more LDLRs, the speed
should be faster than that of its inhibition of endogenous cholesterol
synthesis, then the result would contradict their lipid-lowering effects
and anticancer results in clinic.
Hence, the key may be the
reconstruction of balance of endogenous and exogenous cholesterol
synthesis, and the main strategy for this problem should focus on two
aspects, decreasing endogenous cholesterol synthesis and reducing the
concentration of exogenous cholesterol or targeting LDL receptors. In
addition, statins can re-polarize
tumor-associated macrophages (TAM)
via reducting cholesterol to increase tumor necrosis factor (TNF)-α, but
to decrease transforming growth factor (TGF)-β, which suppresses
epithelial-to-mesenchymal transition
(EMT) (a biological process by epithelial cells losing their cellular
identity and acquiring a mesenchymal phenotype, involving cancer
metastasis)[20]. Moreover, combination of
cholesterol and its G protein-coupled receptor (GPCR) can activate
the Hedgehog (HH) pathway that has
been proved an extraordinary promotion for the development of
EOC[21]. Statins is confirmed to reduce
proliferation of medulloblastoma cells by reduction of cholesterol
systhesis to inhibit HH pathway[22], but whether
statins fighting against ovarian cancer by the mechanism is necessary to
establish further.
2.2 MVAP beyond
cholesterol systhesis
In addition to cholesterol biosynthesis, the MVAP is a crucial metabolic
pathway for numerous cellular activities[23],
and HMGCR on which is a drug target
of statins. In EOC, HMGCR is also established as a metabolic oncogene,
improving tumor development, and commonly seen in OC cells with the TP53
mutation[24]. Thus the inhibition of statins for
it should achieve a good anti-ovarian cancer effect in theory.
Meanwhile, statins decreases the production of farnesyl pyrophosphate
(FPP) and geranylgeranyl pyrophosphate (GGPP) by inhibiting
HMGCR[25], which effect guanosine-triphosphate
hydrolase (GTPases), such as Ras and Rho, that participate in
proliferation, migration and cell invasion[26],
and then farnesylation is unable to complete, which can make the protein
non-polar to achieve cell membrane anchoring. Indeed, MVAP can also
restrain EMT without cholesterol.
Kato S.et al. demonstrated that statins revamped the stemness and EMT
marker expression patterns (both in mRNA and protein levels) in ovarian
cancer by the MVAP inactivating of the Hippo/YAP/Rho
pathway[27]. Therefore, statin can restrict the
proliferation and metastasis of EOC. Moreover, the results after
knocking out the hydroxymethylglutaryl (HMG) metabolic target were
similar to those of statins, further confirming that statins can inhibit
ovarian cancer progression through the MVAP[28].
2.3Voltage-dependent anion
channel 1 ( VDAC1)
The mitochondrial porins, called
voltage dependent anionic channels (VDAC) plays a main role in selective
permeability, which contributes to constant exchange of metabolites and
ions with the cytoplasm through the external mitochondrial membrane
(MOM)[29]. Among VDAC isoforms in mammals, namely
VDAC1, VDAC2, and VDAC3, VDAC1 is
the most characteristic one, serving as an essential gate for
metabolites in the MOM (ATP/ADP, NAD+/NADH, Krebs cycle’s intermediates,
cholesterol and glutamate), and taking part in cholesterol distribution
and in fatty acid transport across the MOM, meanwhile, modulating the
flow of small ions (Cl−, K+, Na+, and Ca2+)[30].
What’s more, it is acknowledged as a regulator of apoptosis. Under the
stimulation of apoptosis, VDAC1 interacts with the pro-apoptotic protein
Bax to form a channel that promotes the release of cytochrome c (CYT c)
to the cytoplasm to activate apoptosis[31].
It is found that VDAC1 is upregulated in OC cell lines but not in normal
cell line and has been proved as a gene related positively with statin
response in OC cells[32]. Meanwhile, VDAC1 can be
regulated by statins, which binds to hexokinase (HK), the rate-limiting
enzyme of glycolysisIt, to play a role in the interconnection between
mitochondrial respiration and the regulation of glycolysis, likely to be
a potential therapeutic target in OC[33].
2.4 The
PI3K/AKT/ mTOR signal
pathway
The control of cell survival, growth, proliferation, angiogenesis,
transcription, translation, and metabolism is largely dependent on the
PI3K/AKT/mTOR signaling pathway[34]. It is
overexpressed in 45% of high-grade serous ovarian cancer (HGSOC) and
can promote OC cells proliferation and
anti-apoptosis[35]. The study of J. Huang, L and
co-workers implies a close connection of specific genetic aberrations in
OC cell lines with siRNA targeting components in the PI3K/AKT/mTOR
signaling pathway[36]. The PI3K/Akt/mTOR signaling
pathway also activates sterol regulatory element binding protein
(SREBPs) transcription to promote cholesterol uptake and synthesis to
meet the needs of cancer cells[37]. Exactly,
statins have a link with this pathway, which are observed that act on
cancer cells can inhibit PI3K/AKT activation to promote the expression
of PTEN[38].
And they can depend on mTOR to inhibit Akt phosphorylation and nuclear
translocation, then to sensitize p53-deficient cells to cytostatic drugs
in hepatocellular carcinoma HepG2 cells and non-small cell lung cancer
cells[39]. Moreover, Stine et al. point out that
simvastatin blocks the PI3K/AKT pathway in SKOV3 and HEY cellst to
increase the active oxygen level to cause DNA damage and to reduce the
vascular endothelial growth factor (VEGF) expression, to induce
endoplasmic reticulum (ER) stress, having an anti-proliferation and
metastasis effect on ovarian cancer[40].
The synergies of statins and antitumor therapies in OC
3.1 Paclitaxel and platinum
Paclitaxel and platinum are well-known anticancer agents, the former by
interfering with spindle formation to promote tubulin polymerization and
to block mitosis at the metaphase-anaphase
transition[41], the latter binding to DNA by the
formation of intra-stranded and inter-stranded crosslinks to kill tumor
cells as main mechanism. Cisplatin, carboplatin, and oxaliplatin, as
platinum-based anticancer drugs, with remarkable therapeutic effects,
are widely used in the clinic.
Statins combined with cisplatin can arrest cell cycle and induce
premature apoptosis, with accompanied dysregulation of Ras pathway
proteins, finally resulting in synergistic reduction in ovarian cancer
cell proliferation[42].
Robinson,E.et
al. found that if simvastatin was administered together with either
carboplatin or paclitaxel, additive effects were seen in the inhibition
of autophagosome trafficking in human ovarian cancer cell lines;
however, when simvastatin was given before carboplatin, strong
antagonism was observed[43]. Actually,
the plasma concentration of statin
obtained in this context is inadequate to counteract the effect of
carboplatin, implying that this is not a significant
issue[43]. It also remind us that would be better
to study how to increase the concentration of statins in the ovaries.
There have also been many experimental studies of statins combined with
paclitaxel or platinum-based drugs for other cancers. The simvastatin’s
combination with paclitaxel remarkably augments efficacy in cellular
system and xenograft mouse model of cervical cancer by by depleting
GGPP, inhibiting prenylation, decreasing GTPases
activities[44].
Lovastatin can sensitize cells to
paclitaxel and dampen metastatic spread by depleting caveolin-1 or
inhibiting MVAP from destroying lipid rafts, then decreasing the
metastatic-potential and chemoresistance in CD133 Hipancreatic tumor
initiating cells[45]. Combination therapy of
low-dose paclitaxel and fluvastatin reduced cell viability and induced
apoptosis by forming DNA fragmentation in primary meningioma cell
culture[46]. It is discovered that combined action
of lovastatin and paclitaxel resulted in upgraded mitosin levels and
that lovastatin changed the association of mitosin with condensed
chromosomes, in the human leukemia K562 and HL-60 cell
lines[47].
What’s more, with regard to drug resistence, it was revealed that
simvastatin can inhibit FAK signaling pathway to resensitize the
drug-resistant cancer cells to paclitaxel, by destroying lipid rafts,
cholesterol-rich domains, and suppressing integrin-β3 and focal adhesion
formation[48].
In terms of drug side effects, rosuvastatin and duloxetine bring down
mechanical allodynia and thermal hyperalgesia in mice treated with
paclitaxel.[49] Simvastatin and rosuvastatin may
have a protective effect against cisplatin-induced kidney and liver
damage via amelioration of lipid peroxidation as well as due to
improvement of kidney and liver function, and lipid-lowering effects in
rats[50]. These potential beneficial results imply
a bonus to protect normal organs for statins except for anti-cancer
effects.
3.2 Bevacizumab
Bevacizumab is a monoclonal antibody to inhibit
VEGF.
By linking with VEGF-A, bevacizumab obstructs the link between VEGF-A
and VEGFR, thus preventing the VEGF signalling pathways that stimulate
neovascularization[51]. It prolongs progression
free survival (PFS) when added to first-line chemotherapy, and to
platinum-sensitive disease. Bevacizumab has also shown activity in
platinum-resistant ovarian cancer (PROC). Early treatment of PROC with a
combination of bevacizumab and chemotherapy allows most patients to
benefit from anti-angiogenic therapy[52].
The investigation of the relationship between statins and angiogenesis
has been done, and interestingly, the effects of HMG-CoA reductase
inhibition on angiogenesis is biphasic dose-dependent, proangiogenic at
low therapeutic concentrations but reversed by GGPP at high, which is
related with alterations in VEGF signaling and endothelial
apoptosis[53].
Even though low-dose statins may
have a little effect on angiogenesis or tumor growth, they are still
thought to increase the sensitivity of cancer cells to signalling
chemotherapy[54].
This may explain why some clinical
studies favor low-dose, continuous statin therapy over short-dose,
high-dose statin therapy, but this does not lead to more complete and
valid conclusions[55].
Therefore, theoretically, it can be inferred that bevacizumab and
statins have a certain synergistic effect on anti-cancer. In a study of
Lee et al., statins (simvastatin, lovastatin, atorvastatin, and
pravastatin) in combination with bevacizumab directly suppress
angiogenic mediators, such as angiopoietin2, binding immunoglobulin
protein (BiP), and Hsp90a, to reduce the cell viability, migration,
invasion, and tube formation of human umbilical vein endothelial cell.
The synergy of bevacizumab with simvastatin obviously weakens the growth
and metastases of xenograft tumours in contrast to with bevacizumab
alone[56].
Although there is a lack of relevant studies on the treatment of ovarian
cancer by statin combined with bevacizumab, the above theories and
studies imply the potential of this
combination therapy as a new research direction.
3.3 Poly ADP-ribose
polymeraseb (PARP) inhibitors
( PARP-is)
PARP-is became the first targeted treatment for HGSOC, selectively
active for women with double-strand
DNA break repair (BRCA) mutations and/or a homologous recombination (HR)
deficiency (HRD) phenotype up to 50% of
cases[57]. Mostly, PARP inhibitors eliminate
selectively cancer cells through DNA damage accumulation, after block
the single-strand DNA break repair process in BRCA1/2 and/or HRD cancer
cells, while unaffecting normal cells with an intact double-strand DNA
break repair system[57]. With further clinical
trials of olaparib, niraparib and rucaparib, they usually cause a good
initial response, and treatment landscape hasn’t been limited to a
subgroup of women with relapsed ovarian cancer, which has shifted to
the first-line maintenance therapy
setting[60], but many patients develop resistance
to PARP-is and appear disease
progression or relapse of tumor cells[57].
According to the experimental and clinical results on PARP-is activating
AKT under oxidative stress conditions[61], it
emphasizes Akt activation that is critical in the cytoprotective
properties of PARP1 inhibition, which can undermine the cellular
inhibitory effect of PARP1 inhibitor on cancers carrying BRCA mutations.
Reports about the increase of PARP-is’ cytotoxicity by Akt inhibitor
support this notion[62].
As experimental evidences in vitro
and in vivo indicate that inhibition of PARP1 can activate the
cytoprotective PI3K-Akt pathway, which induce mitochondrial protection
and apoptosis resistance that contribute to the limitation of cytostatic
efficacy in PARP-is therapy[63].
Actually, many studies on the anti-cancer mechanism of statins have
proved that they are inhibitors of AKT, that is, they reduce the
phosphorylation of AKT to inhibit the proliferation of cancer
cells[64]. A study indicates that statin-induced
inhibition of Akt phosphorylatio can sensitize cells to cytostatic
drugs. This mechanism appears to occur only in cancer cells, whereas in
normal cells statins activate the AKT pathway for cell protection. To a
certain extent, the overlapping results of these studies suggest that
statins may counteract parp inhibitor resistance through AKT signaling
pathway, and the potential as a new combination therapy for ovarian
cancer, which needs to be confirmed in further experiments and clinical
trials.