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.