Targets of statins in cancer
| Tumor (cell type) | Statin | Effect | Mechanism of action | Reference |
|---|---|---|---|---|
| Breast cancer (MCF-7, ZR75T, MDA-MB-157, Hs578T, T47D, MDA-MB-231) | Lovastatin | Inhibition of cell proliferation | Cell cycle arrest at G1 phase; decrease of CDK2 activity through redistribution of p21Waf1/Cip1 and p27Kip1 from CDK4 to CDK2 | Rao et al. (1998) |
| Breast cancer (MDA-MB-231) | Cerivastatin | Reduction of cell proliferation and invasiveness | Inhibition of RhoA-dependent cell signaling; down-regulation of cyclin D1, PCNA, c-myc, u-PA, MMP-9, u-PAR, PAI-1; up-regulation of p21Waf1, p19Ink4d, integrin β8, Wnt-5a | Denoyelle et al. (2003) |
| Breast cancer (MCF-7, SKBr3, MDA-MB-231) | Fluvastatin, lovastatin, simvastatin | Inhibition of cell growth | Transient decrease in p-MEK1/2; increase of IκBα and p21; decrease of cyclin D1, Bcl-2, and Bcl-xL | Campbell et al. (2006) |
| Breast cancer (MCNeuA cell line injected in female neuTg mice) | Simvastatin, fluvastatin (orally administered) | Inhibition of tumor growth in vivo | Reduction of tumor volumes; induction of central necrosis; induction of caspase-3 cleavage | |
| Breast cancer (MCF-7, MDA-MB-231) | Simvastatin | Inhibition of cell proliferation | Induction of cell cycle arrest and apoptosis; activation of JNK and increased phosphorylation of c-Jun | Koyuturk et al. (2007) |
| Colon carcinoma (HCT116, SW480, LoVo, HT29) | Lovastatin | Inhibition of cell proliferation | Induction of apoptosis; decrease of bcl-2 and increase of bax protein expression | Agarwal et al. (1999) |
| Glioblastoma multiforme (primary cell cultures from biopsies) | Lovastatin | Inhibition of cell proliferation and migration | Reduction of MAPK activity; induction of apoptosis; disruption of actin cytoskeleton | Bouterfa et al. (2000) |
| Glioblastoma multiforme (U87, U251) | Inhibition of cell proliferation | Activation of ERK1/2, c-Jun, and p38; up-regulation of Bim and induction of apoptosis | Jiang et al. (2004) | |
| Leukemia (Jurkat, CEM, IM9, U266) | Lovastatin, simvastatin, pravastatin, cerivastatin, atorvastatin | Inhibition of cell proliferation | Induction of apoptosis through cytosolic release Smac/DIABLO and activation of caspases 9, 3, and 8 | Cafforio et al. (2005) |
| AML (OCI-AML-1, OCI-AML-2, OCI-AML-3, OCI-AML-4, and OCI-AML-5) and primary cell cultures from patients with AML | Lovastatin | Inhibition of cell proliferation | Induction of apoptosis | Dimitroulakos et al. (1999) |
| AML cell lines | Lovastatin (low doses) | Induction of differentiation | Down-regulation of bcl-2; increase of the leukocyte integrin CD11b and CD18 expression | Dimitroulakos et al. (2000) |
| Acute Promyelocytic Leukemia (NB4) | Atorvastatin, fluvastatin | Inhibition of cell proliferation | Induction of cell differentiation and apoptosis; activation of Rac1/Cdc42 and of JNK pathway | Sassano et al. (2007) |
| Leukemic progenitors (primary bone marrow–derived from patients with AML) | Fluvastatin | Inhibition of leukemic CFU-GM colony formation | ||
| Promyelocytic leukemia (HL60 intravenously inoculated in SCID mice) | Simvastatin (subcutaneous continuous infusion) | Inhibition of cell proliferation in vivo | Reduction of the clonogenic cells in bone marrow and spleen of mice (Ras-independent mechanism). | Clutterbuck et al. (1998) |
| Promyelocytic leukemia (HL60) | Lovastatin | Inhibition of cell growth | Induction of apoptosis through release of mitochondrial cytochrome c and caspase-3 activation. | Wang et al. (2000) |
| Melanoma (A375M, SK-Mel 128, CHL, WM-166–4) | Atorvastatin | Alteration of melanoma cells morphology and inhibition of cell proliferation; inhibition of melanoma cell invasion | F-actin depolymerization and disassembly of stress fibers; up-regulation of RhoA and Rho exclusion from the membrane; increase of p21Waf1/Cip1 and p27Kip1. | Collisson et al. (2003) |
| Melanoma (A375M injected in tail vein of SCID mice) | Atorvastatin (orally administered) | Inhibition of colonization and formation of metastatic lesions in the lung in vivo | Inhibition of the effects induced by RhoC overexpression. | |
| Myeloma (MCC-2) | Cerivastatin | Inhibition of cell proliferation | Induction of apoptosis through caspases activation; delocalization from membrane to cytosol of Rho and Ras | Cafforio et al. (2005) |
| Pancreatic cancer (PANC-1) | Fluvastatin, lovastatin | Inhibition of EGF-induced migration and invasiveness | Inhibition of RhoA translocation from cytosol to membrane; inhibition of actin stress fiber assembly | Kusama et al. (2001) |
| Prostate cancer (LNCaP) | Lovastatin | Inhibition of cell proliferation | Induction of apoptosis through proteolytic activation of caspase 7 | Marcelli et al. (1998) |
| Anaplastic thyroid cancer (ARO) | Lovastatin | Inhibition of cell proliferation | Induction of apoptosis (higher doses) | Wang et al. (2003) |
| Induction of differentiation (lower doses) | ||||
| Reduction of EGF-induced invasiveness | Reduction of phosphorylated p125 (FAK) and paxillin; inhibition of RhoA and Rac1 geranylgeranylation and membrane translocation | Zhong et al. (2005) | ||
| Thyroid cancer (KiMol) | Lovastatin | Inhibition of cell proliferation | Induction of apoptosis; modulation of the cellular redox state | Bifulco (2008); Laezza et al. (2008) |
| Cytoskeletal disorganization | Bifulco (2005) |
PCNA, proliferating cell nuclear antigen; u-PA, urokinase plasminogen activator; MMP-9, matrix metalloprotease-9; u-PAR, urokinase plasminogen activator receptor; PAI-1, plasminogen activator inhibitor-1; IκBα, inhibitor of nuclear factor-κBα; Smac/DIABLO, second mitochondria-derived activator of caspases/direct IAP binding protein with low PI; CFU-GM, colony-forming units-granulocyte macrophage; FAK, focal adhesion kinase; MCNeuA, mammary carcinoma from Neu transgenic mouse A.