Statins in risk-reduction and treatment of cancer

Table 1 In vitro studies on the anticancer potential of statins

Cancer type	Cancer cell line	Statin	Observations	Changes in intracellular signaling pathways	Ref.
Hepatoma	HepG2, Hep3B	Simvastatin	Inhibition of cell growth in a dose- and time-dependent manner; G0/G1 cell cycle arrest; Apoptosis	AMPK activation and STAT3/Skp2 axis suppression, inducing p21 and p27 accumulation	[21]
Ovarian cancer	Hey, SKOV3	Atorvastatin	Dose-dependent antiproliferative effect (1-250 µmol/L); Decrease in size and density of the cancer cells, and colony forming ability (at 150 µmol/L); G1-phase cell cycle arrest and S-phase decrease (at 150 µmol/L); Induction of apoptosis; Increased ROS levels in a dose-dependent manner; Induction of autophagy; Inhibition of cell adhesion and invasion	Inhibition of Akt/mTOR and activation of MAPK pathway; Decreased Mcl-1 expression, variable effect on Bcl-2 expression, increased cleaved PARP protein expression; Increased expression of cellular stress protein (PERK and Bip) (at 150 µmol/L); Reduced expression of VEGF protein and MMP-9	[22]
Breast cancer	SUM149, SUM159, MDA-MB-231	Simvastatin	Inhibition of proliferation, decrease in S-phase and increase in G1/S-phase arrest; Suppression of cell migration; Decrease in tumor sphere formation	Down-regulation of phosphorylated FOXO3a in SUM149 and SUM159 cells; Variable effect on total FOXO3a expression	[43]
Endometrial cancer	ECC-1, Ishikawa, primary cultures of endometrial cancer cells	Simvastatin	Dose-dependent antiproliferative effect in both cancer cell lines (0.01-50 µmol/L), and in 5/8 primary cultures; G0/G1-phase cell cycle arrest, decreased S-phase in ECC-1 cells; Decreased HMG-CoA reductase activity; Induction of apoptosis; Increased DNA damage, cellular oxidative stress; Reduced cell adhesion and invasion	Inhibition of MAPK pathway, differential effects on the Akt/mTOR pathway; Increased cleaved caspase-3, decreased Bcl-2 expression, unmodified Mcl-1	[20]
Osteosarcoma	MNNG/HOS	Simvastatin	Dose- and time-dependent antiproliferative effect (0.5-64 µmol/L); Dose-dependent morphological changes in treated cells: Cell shrinkage, loss of intercellular contact, reduced cell adherence, floating shapes; Dose-dependent suppression of cell migration, G0/G1-phase cell cycle arrest (16 µmol/L), and apoptosis	Dose-dependent down-regulation of MMP-2 and MMP-9; Down-regulation of cyclin D1, CDK2 and CDK4, up-regulation of CDKIs, p21 Cip1 and p27 Kip1; Decrease in PI3K and phospho-Akt expression, while total AKt remained unmodified, up-regulation of Bax and cleaved PARP expression, decreased Bcl-2 expression	[44]
Lung adenocarcinoma	A549, H1299, PC9, HCC827, H1975, H1435, PE8sc, CL1-0, Bm7, and immortalized normal lung epithelial cells (HBEC3KT)	Simvastatin	Higher cytotoxicity against LC cells with p53 mutation; Dose-dependent apoptosis; Reduced lipid rafts in mutant p53-bearing LC cells; Reduction in the migration distance; Promotes the nuclear transport of mutant p53 in Bm7 and H1435 cells	Increased levels of cleaved PARP and cleaved caspase-3; No difference in the level of LC3-II; Decreased level of p53, and increased level of high molecular weight HSP-40	[45]

MAPK: Mitogen-activated protein kinase; ROS: Reactive oxygen species; HMG-CoA reductase: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; AMPK: AMP-activated protein kinase; STAT3: Signal transducer and activator of transcription 3; skp2: S-phase kinase associated protein 2; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; PARP: Poly (ADP-ribose) polymerase; VEGF: Vascular endothelial growth factor; MMP: Matrix metalloproteinase; CDK: Cyclin-dependent kinase; CDKI: Cyclin-dependent kinase inhibitor; PI3K: Phosphoinositide 3-kinase; LC3: Microtubule-associated protein 1A/1B-light chain 3.

Table 2 A summary of recent meta-analyses evaluating the benefits of statins in various types of cancer

Cancer type	No. of clinical trials and subjects included	Objective	Results	Ref.
Active cancer	Ten studies, 1881 individuals with stage 3 or higher disease	To evaluate the randomized controlled trials of statins in addition to standard anticancer therapy	The addition of statins to standard anticancer therapy did not improve overall survival or progression-free survival	[105]
Solid cancer	Eight randomized controlled trials, 1760 patients	To evaluate the effect of statins added to systemic anticancer therapy in patients with solid cancer	The addition of statins to chemotherapy did not significantly increase the incidence of grade 3-5 adverse events, did not improve the overall response rate and failed to prolong the progression-free survival and overall survival compared with that of chemotherapy alone	[106]
Pancreatic cancer	Six retrospective cohort studies, 12057 patients were included	To explore the association between statin and metformin use and overall survival of pancreatic cancer patients	Statin use was associated with a significantly improved overall survival (but with a significant publication bias)	[107]
	Twenty-six studies, more than 3 million participants, 170000 pancreatic cancer patients	The relationship between statin use and the risk of pancreatic cancer	Statins have a protective effect on pancreatic cancer	[108]
Kidney cancer	Twelve studies, 18105 patients	To evaluate the association between statin use and kidney cancer survival outcomes	Statin use was not associated with significant recurrence-free survival or progression-free survival; statin use was associated with marked improvements in cancer-specific survival and overall survival	[109]
Lung cancer	Seventeen studies, 98445 patients	To analyze the impact of statins on mortality and survival of LC patients	Statins were potentially associated with a decreased risk of mortality and an improvement of overall survival in observational studies but not in randomized controlled trials; Statins potentially enhanced the effects of tyrosine kinase inhibitors and chemotherapy on the overall survival of patients with non-small cell LC	[110]