Table 3 The anti-cancer effect of statins in preclinical studies

Breast cancers

Simvastatin

In vitro

0–1000 μM

-

Simvastatin induces the apoptosis of MCF-7 cells by increasing caspase-3 and Bax expression

[70]

Simvastatin

In vitro

0–150 μM

-

Simvastatin induces apoptosis, suppress proliferation and dephosphorylate sequential signaling cascades of PI3K/Akt/mTOR and MAPK/ERK pathways of breast cancer

[71]

Atorvastatin

In vitro

0–80 μM

-

The anti-proliferative effect of atorvastatin on breast cancer cells is mediated by the induction of both apoptosis and autophagy

[72]

Simvastatin

In vitro

0–200 μM

-

Simvastatin induces apoptosis via involvement of JNK in breast cancer cells independent of their ER or p53 expression status

[73]

Lovastatin

In vitro

0–50 μM

-

Lovastatin activates LKB1-AMPK-p38MAPK-p53-survivin cascade to cause MCF-7 cell death

[74]

Simvastatin

In vitro

0–5 μM

-

Simvastatin increased the expression of miR-140-5p in a dose dependent manner via activating transcription factor NRF1, reduced cell proliferation and induced apoptosis

[75]

Simvastatin

In vitro

0–100 μM

-

Simvastatin showed the reduction in DNA synthesis and induced cell cycle arrest in the G1 phase in MCF-7 CSCs

[76]

Mevastatin

In vitro and vivo

0–16 μM (In vitro)

10 mg/Kg (In vivo)

Histone deacetylase inhibitors (HDACi)

Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7

[77]

Simvastatin

In vitro

0–100 μM

Doxorubicin

Simvastatin acts synergistically with the anticancer drug doxorubicin against MCF-7 cells through a downregulation of the cell cycle or induction of apoptosis

[78]

Simvastatin

In vitro

0–100 μM

Pentoxifylline

The combined use of pentoxifylline and simvastatin may drive dormant autophagic cancer cells to undergo apoptosis

[79]

Simvastatin

In vitro and vivo

0–10 μM (In vitro)

5 mg/kg (In vivo)

-

Simvastatin induces derepression of PTEN expression via NF-κB to inhibit breast cancer cell growth

[80]

Lovastatin

In vitro

0–100 μM

-

Lovastatin treatment down-regulates the expression of Bcl-2 and activates apoptosis through a mitochondria-operated, ErbB2- regulated mechanism

[81]

Prostate cancer

Simvastatin and fluvastatin

In vitro

0–10 μM

-

Statins decrease cell proliferation and induce cell apoptosis, probably mediated via a downregulation of AKT/FOXO1 phosphorylation in prostate cancer cells

[82]

Simvastatin

In vitro

0–50 μM

Irinotecan

Combined treatment of simvastatin with irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis via inhibition of MCL-1

[83]

Atorvastatin

In vitro

0–50 μM

Irradiation

Atorvastatin enhances the radiosensitivity of hypoxia-induced prostate cancer cells by decreasing the expression of HIF-1α protein

[84]

Atorvastatin

In vitro

0–5 μM

Caffeine

The combination of atorvastatin and caffeine suppressed proliferation and induced apoptotic death by downregulating phospho-Akt, phospho-Erk1/2, anti-apoptotic Bcl-2 and Survivin protein levels

[85]

Simvastatin

In vitro and vivo

0–100 μM (In vitro)

2 mg/kg (In vivo)

-

Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression

[86]

Atorvastatin

In vitro and vivo

0–10 μM (In vitro)

5 mg/kg or

10 mg/kg (In vivo)

Celecoxib

The combination of atorvastatin and celecoxib more strongly inhibited growth and the activation of Akt, Erk1/2 and NF-κB in cultured LNCaP cells than either agent alone. In addition, administration of a combination of celecoxib and atorvastatin had a strong inhibitory effect on the progression of androgen-dependent LNCaP prostate tumors to androgen independence in castrated severe combined immunodeficient (SCID) mice

[87]

Atorvastatin, mevastatin, simvastatin and rosuvastatin

In vitro

0–10 μM

-

Statins reduce the migration and colony formation of PC-3 cells in human bone marrow stroma by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies

[88]

Atorvastatin

In vitro

0–10 μM

-

Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription

[89]

Lovastatin and simvastatin

In vitro

0–2 μM

-

Lovastatin and simvastatin induced apoptosis and cell growth arrest in the G1 phase by inactivating RhoA

[90]

Pancreatic cancer

Pitavastatin

In vitro and vivo

0–0.5 μM (In vitro)

5 mg/kg (In vivo)

Gemcitabine

The combination of gemcitabine and pitavastatin synergically suppressed the proliferation of MIA PaCa-2 cells through causing sub-G1 and S phase cell cycle arrest, activated autophagy and effectively inhibited tumor growth in a nude mouse mode of Mia PaCa-2 xenografts

[91]

Gastric cancer

Simvastatin

In vitro

0–100 μM

-

Simvastatin inhibited the proliferation and migration of NCI-N87 and Hs746T cell lines by reducing mevalonolactone, FPP and GPP

[92]

Simvastatin

In vitro

0–60 μM

-

Simvastatin inhibits the malignant behaviors of gastric cancer cells by simultaneously suppressing YAP and β-gatenin signaling

[93]

Colorectal cancer

Simvastatin

In vitro

0–20 μM

-

Simvastatin induces the apoptosis of human colon cancer cells and inhibits IGF-1-induced ERK and Akt expression via the downregulation of IGF-1R expression and proapoptotic ERK activation

[94]

Simvastatin

In vitro and vivo

0–50 μM (In vitro)

20 mg/kg (In vivo)

-

Simvastatin activates the p38MAPK-p53-survivin cascade to cause HCT116 colorectal cancer cell apoptosis

[95]

Atorvastatin

In vitro and vivo

0–18 μM (In vitro)

15 mg/kg (In vivo)

Nobiletin

Nobiletin/atorvastatin co-treatment synergistically induced extensive cell cycle arrest and apoptosis in colon cancer cells, and the enhanced chemopreventive activities against colon carcinogenesis in rats by the nobiletin/atorvastatin combination were highly synergistic

[96]

Liver cancer

Fluvastatin and pravastatin

In vitro

Fluvastatin: 0–50 μM

Pravastatin: 0–500 μM

PBR ligand

Statins inhibited the proliferation of HCC cells by inducing apoptosis and G1/S cell cycle arrest, and the efficacy of treatment with statins was synergistically enhanced by ligands of the peripheral benzodiazepine receptor (PBR)

[97]

Atorvastatin

In vitro and vivo

0–40 μM (In vitro)

20 mg/kg (In vivo)

-

Atorvastatin induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway

[98]

Atorvastatin

In vitro

0–30 μM

-

Atorvastatin mediated cell death occurred via inhibition of the PI3K/Akt pathway

[99]

Simvastatin

In vitro and vivo

0–40 μM (In vitro)

20 mg/kg (In vivo)

-

Simvastatin induced cell cycle arrest through inhibition of STAT3/SKP2 axis and activation of AMPK to promote p27 and p21 accumulation in hepatocellular carcinoma cells

[100]

Pitavastatin

In vitro

0–20 μM

-

Pitavastatin inhibited growth and colony formation of liver cancer cell, and induced arrest of liver cancer cells at the G1 phase, furthermore, Pitavastatin promoted caspase-9/-3 cleavage in liver cancer cells

[101]

Simvastatin

In vitro

0–20 μM

Receptor- interacting protein 140

Simvastatin induced the apoptosis of SMCC-7721 cells through the Wnt/β-catenin signaling pathway, as well as that receptor-interacting protein 140 and simvastatin exert a synergistic effect on the inhibition of cell proliferation and survival

[102]

Ovarian cancer

Lovastatin and atorvastatin

In vitro

0–20 μM

-

Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression

[103]

Lovastatin

In vitro and vivo

0–100 μM (In vitro)

12.5 mg/kg (In vivo)

-

Lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways

[104]

Lung cancer

Pitavastatin and fluvastatin

In vitro

0–100 μM

Erlotinib

Cytotoxicity mediated by statin/erlotinib co-treatment is synergistic and can overcome erlotinib resistance in K-ras mutated NSCLC and relies only on apoptosis

[105]

Simvastatin

In vitro and vivo

0–100 μM (In vitro)

50 mg/kg (In vivo)

-

Simvastatin potently disrupts growth and survival in human SCLC cells by inhibiting Ras signaling

[106]

Simvastatin

In vitro and vivo

0–1 μM (In vitro)

10 mg/kg (In vivo)

-

Simvastatin prevents proliferation and osteolytic bone metastases of lung adenocarcinoma cells via regulates CD44, P53, MMP family and inactivates of MAPK/ERK signaling pathway

[107]

Simvastatin

In vitro

0–10 μM

-

Statins break the communication between cancer cells and mesenchymal stromal cells (MSCs) by inhibiting CCL3 secreted by cancer cells and IL-6 and CCL2 produced by MSCs

[108]

Lymphoma

Atorvastatin, fluvastatin and simvastatin

In vitro

0–20 μM

-

Statins induce lymphoma cells apoptosis by increasing intracellular ROS generation and p38 activation and suppressing activation of Akt and Erk pathways, through inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP

[109]

Lovastatin

In vitro

0–5 μM

-

Lovastatin inhibits malignant B cell proliferation by reducing membrane cholesterol, intracellular ROS, TRPC6 expression and activity, and intracellular Ca2 + 

[110]

Brain cancer

Simvastatin

In vitro

0–20 μM

-

Simvastatin Induces caspase-dependent apoptosis via the mevalonate pathway

[111]

Simvastatin

In vitro

0–20 μM

Temozolomide

Simvastatin inhibited the autophagy flux induced by temozolomide by blocking autophagolysosome formation

[112]

Melanoma

Simvastatin and atorvastatin

In vitro

0–80 μM

TRAIL

Statins enhanced TRAIL-induced apoptosis, due to suppression of the NF-kB and STAT3-transcriptional targets (including COX-2) and downregulation of cFLIP-L (a caspase-8 inhibitor) protein levels

[113]

Pitavastatin

In vitro

0–5 μM

Dacarbazine

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

[114]

Lovastatin

In vitro

0–4 μM

-

Lovastatin induces apoptosis in multiple melanoma cell lines via a geranylation-specific mechanism through caspase-dependent signaling

[115]

Simvastatin

In vivo

50 mg/kg

-

Statin lowers PD-1 expression in CD8 + T cells and effectively restores antitumor activity

[116]

Esophageal carcinoma

Simvastatin, lovastatin and pravastatin

In vitro

0–100 μM

-

Statins inhibit proliferation and induce apoptosis in EAC cells via inhibition of Ras farnesylation and inhibition of the ERK and Akt signaling pathways

[117]

Bile duct cancer

Simvastatin

In vitro

0–500 μM

-

Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation

[118]

Simvastatin

In vitro

0–100 μM

-

Simvastatin induces cholangiocarcinoma cancer cell death by disrupting Rac1/lipid raft colocalization and depression of Rac1 activity

[119]

Osteosarcoma

Simvastatin

In vitro and vivo

0–5 μM (In vitro)

40 mg/kg, 50 mg/kg or

80 mg/kg (In vivo)

-

Simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK

[120]

Simvastatin and fluvastatin

In vitro

0–5 μM

-

Statins inhibit GGPP biosynthesis in the mevalonate pathway, and then inhibit signal transduction in the Ras/ERK and Ras/Akt pathways, thereby inhibiting bFGF, HGF, TGF-β expression in LM8 cells

[121]

Head and neck squamous cell carcinoma

Lovastatin

In vitro

0–50 μM

-

Lovastatin activates AMPK-p38MAPK-p63-survivin cascade to cause FaDu hypopharyngeal carcinoma cell death

[122]

Lovastatin

In vitro

0–10 μM

Chemotherapeutic drugs (cisplatin, cyclophosphamide, doxorubicin and paclitaxel) and Photodynamic therapy

Lovastatin inhibited the CSC properties and induced apoptosis and cell cycle arrest in 5-8F and 6-10B nasopharyngeal carcinoma cell line, and lovastatin conferred enhanced sensitivity to the chemotherapeutic and photodynamic agents in nasopharyngeal carcinoma CSCs

[123]

Simvastatin

In vitro

0–100 μM

Celecoxib

The combination of celecoxib and simvastatin has showed a significant reduction in tumor cell viability, proliferation and secretion of IL-6 and IL-8

[124]

Simvastatin

In vivo

5 mg/kg or 10 mg/kg

Monocarboxylate transporter 1 inhibitor

Simvastatin induces metabolic reprogramming in HNSCC mice, reducing lactate production and promoting cancer sensitivity to MCT1 inhibitor

[125]

Pitavastatin

In vitro

0–0.5 μM

-

Pitavastatin activates the FOXO3a/PUMA apoptotic axis by regulation of nuclear translocation of FOXO3a via Akt/FOXO3a or AMPK/FOXO3a signaling

[126]

Leukemia

Atorvastatin

In vitro

0–80 μM

-

Atorvastatin exerts antileukemia activity via Inhibiting mevalonate-YAP axis in K562 and HL60 cells

[127]

Simvastatin

In vitro

0–10 μM

-

Simvastatin exhibited anti-leukemic effect in human AML cells in vitro, especially at NRAS^G12D mutant AML cell line

[128]

Simvastatin

In vitro

0–10 μM

Bergamottin

Simvastatin and bergamottin potentially preventing and treating cancer through modulation of NF-kB signaling pathway and its regulated gene products

[129]

Multiple myeloma

Pravastatin

In vitro

0–0.9 μM

-

Pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line

[130]

Simvastatin

In vitro

0–10 μM

-

Simvastatin induced S-phase cell cycle arrest and apoptosis of multiple myeloma cells through the Chk1–Cdc25A-cyclin A/CDk2 pathway

[131]

Kidney cancer

Simvastatin and fluvastatin

In vitro and vivo

0–2 μM (In vitro)

10 mg/kg (In vivo)

Everolimus

Combination statins and mTOR inhibitor induced a robust activation of retinoblastoma protein via inhibits KRAS or Rac1 protein prenylation, and statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models

[132]

Gallbladder cancer

Lovastatin

In vitro and vivo

0–50 μM (In vitro)

50 mg/kg (In vivo)

Cisplatin

Lovastatin sensitized GBC cells to cisplatin-induced apoptosis and suppressed the activation of CHK1, CHK2, and H2AX during DNA damage response, and subcutaneous xenograft mice model suggested lovastatin promoted the therapeutic efficacy of cisplatin, and significantly prolonged the survival times of tumor-bearing mice

[133]

Endometrial cancer

Simvastatin

In vitro

0–12 μM

Metformin

Combination simvastatin and metformin synergistically inhibits endometrial cancer cell viability mediated by apoptosis and mTOR pathway inhibition

[134]