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

From: Statins: a repurposed drug to fight cancer

Cancer Statins Type of study Dose of administration Combination agent Findings Ref.
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 NRASG12D 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]
  1. Abbreviations: AML Acute myeloid leukemia, CSCs Cancer stem cells, EAC Esophageal adenocarcinoma, GBC Gallbladder cancer, HNSCC Head and neck squamous cell carcinoma, MCT1 Monocarboxylate transporter 1, PBR Peripheral benzodiazepine receptor, RCC Renal cell carcinoma, TRAIL TNF-related apoptosis inducing ligand