Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Kamigaki, Michihiro

doi:10.3892/ijo.2011.1087

Cited by 34 publications

(46 citation statements)

References 31 publications

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“…In prostate cancer cells, the two apoptotic pathways are activated by the action of lovastatin and simvastatin, although it seems that the main route is the extrinsic one (52). In cholangiocarcinoma cells treated with pitavastatin and atorvastatin, apoptotic processes by the pathway dependent on mitogen-activated protein kinase (MAPKs) have also been identified (53). In breast cancer cells, some studies have detected the potential antiproliferative effects by statins inducing apoptosis (54).…”

Section: Discussionmentioning

confidence: 99%

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

Martín-Navarro

López-Arencibia

Sifaoui

et al. 2015

Antimicrob Agents Chemother

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cMembers of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a lifethreatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC 50 s) and IC 90 s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba.

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Section: Discussionmentioning

confidence: 99%

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

Martín-Navarro

López-Arencibia

Sifaoui

et al. 2015

Antimicrob Agents Chemother

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“…In addition, statins perform roles in immune regulation (11), the inhibition of inflammation (12) and the modulation of angiogenesis (13). Statins also exhibit anticancer activities (14,15), decrease cellular proliferation (15)(16)(17) and induce apoptosis (15,18,19) in breast, colorectal, lung, prostate and pancreatic cancer (20). Notably, statins inhibit cancer cell growth in vivo and decrease metastasis at clinically therapeutic doses (21).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

2017

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Abstract. Simvastatin is a low density lipoprotein-lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF-7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF-7 cells was evaluated by a sulforhodamine B and colony formation assay. To delineate the mechanisms of cell death, the following parameters were measured: Reactive oxygen species (ROS) production using the fluorescence probe dihydroethidium; caspase 3 activity by the fluorometry method; gene expression by quantitative polymerase chain reaction; and apoptotic-and proliferative-related protein levels by western blotting. MCF-7 cell proliferation was significantly suppressed by 24-48 h treatment with simvastatin alone. Doses of 10-50 µM simvastatin also enhanced the cytotoxicity of doxorubicin against MCF-7 cells in a dose-dependent manner, and decreased the colony-forming ability of MCF-7 cells. Simvastatin alone or in combination with doxorubicin significantly increased ROS levels. Combination treatment significantly decreased expression of the cell cycle regulatory protein Ras-related C3 botulinum toxin substrate 1 and numerous downstream proteins including cyclin-dependent kinase (Cdk) 2, Cdk4 and Cdk6. Additionally, simvastatin in combination with doxorubicin significantly induced expression of the cyclin-dependent kinase inhibitor p21, increased cytochrome c and caspase 3 expression and reduced cyclin D1 expression. In conclusion, simvastatin acts synergistically with the anticancer drug doxorubicin against MCF-7 cells, possibly through a downregulation of the cell cycle or induction of apoptosis. Although additional studies are required, simvastatin and doxorubicin combination may be a reasonable regimen for the treatment of breast cancer.

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“…Reliable evidence from in vitro and in vivo data has demonstrated that statins exert pleiotropic actions beyond their lipid-lowering effects, including in cancer prevention and treatment (6,18). Previous studies have also reported that statins trigger cancer cell apoptosis in various cancer cell types (19,20). The results from the present study revealed that short-time use of low-dose simvastatin had a very limited effect in inhibiting cell viability and inducing cell apoptosis at 24 h following treatment.…”

Section: Discussionmentioning

confidence: 85%

Enhanced antitumor effects of low-frequency ultrasound and microbubbles in combination with simvastatin by downregulating caveolin-1 in prostatic DU145 cells

Xu¹,

Shen²,

Bai³

et al. 2014

Oncology Letters

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Advanced prostate cancer is difficult to treat due to androgen resistance, its deep location and blood tumor barriers. Low-frequency ultrasound (LFU) has potential clinical applications in the treatment of prostate cancer due to its strong penetrability and high sensitivity towards tumor cells. Simvastatin has often been administered as a preventive agent in prostate tumors. The aim of the present study was to investigate the enhanced effects of LFU and microbubbles in combination with simvastatin, in inhibiting cell viability and promoting apoptosis of androgen-independent prostatic DU145 cells. Cultured DU145 cells were divided into six groups based on the combination of treatments as follows: Control, LFU, LFU and microbubbles (LFUM), simvastatin, LFU and simvastatin, LFUM and simvastatin. The cells were treated by LFU (80 kHz) continuously for 30 sec with an ultrasound intensity of 0.45 W/cm2 and a microbubble density of 20%. Simvastatin was added 30 h prior to the ultrasound exposure. The results indicated that cell viability was marginally reduced in the LFU and simvastatin alone treatment groups compared with the control 24 h following ultrasound exposure. The combination of LFU, with microbubbles or simvastatin, potentiated the growth inhibition; the greatest inhibition was observed in the cells that were subject to treatment with LFUM and simvastatin in combination. Furthermore, this inhibitory effect was enhanced in a time-dependent manner. For cell apoptosis, a low dose of simvastatin had no apparent affect on the DU145 cells, while LFU marginally promoted cell apoptosis. Microbubbles or simvastatin increased the apoptosis rate of the DU145 cells, however, the combination of LFUM and simvastatin induced a strong synergistic effect on cell apoptosis. Western blotting analysis demonstrated a high expression level of caveolin-1 in resting DU145 cells. LFUM or combined LFU and simvastatin resulted in a greater reduction in the expression compared with the control group (P<0.05). The expression of caveolin-1 was lowest in the LFUM combined with simvastatin treatment group. The expression of phospho-Akt (p-Akt) was consistent with caveolin-1, with the lowest expression levels of p-Akt observed in the cells that were treated with the combination of LFUM and simvastatin. The results indicate that LFUM in combination with simvastatin may additively or synergistically inhibit cell viability and induce apoptosis of DU145 cells by downregulating caveolin-1 and p-Akt protein expression.

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Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Cited by 34 publications

References 31 publications

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

Simvastatin potentiates doxorubicin activity against MCF‑7 breast cancer cells

Enhanced antitumor effects of low-frequency ultrasound and microbubbles in combination with simvastatin by downregulating caveolin-1 in prostatic DU145 cells

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