Ciglitazone, an agonist of peroxisome proliferator-activated receptor γ, exerts potentiated cytostatic/cytotoxic effects against tumor cells when combined with lovastatin

Mrówka, Piotr; Głodkowska, Eliza; Nowis, Dominika; Legat, Magdalena; Issat, Tadeusz; Makowski, Marcin; Szokalska, Angelika; Janowska, Sylwia; Stokłosa, Tomasz; Jakóbisiak, Marek; Gołąb, Jakub

doi:10.3892/ijo.32.1.249

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…Recently, statins were evaluated for their protective effects in cancer and showed antiproliferative and pro-apoptotic effects in vitro [ 106 – 108 ]. Incubation with lovastatin and CIG for 48 hrs exerted additive cytotoxic and cytostatic effects in multiple cancer cell lines (Panc 02 and MIA PaCa-2 pancreatic cancer, C-26 colon cancer, and EMT6 and MDA-MB-361 breast cancer) compared to either treatment alone [ 49 , 50 ]. Further experiments on human U87, U138, LN 405, and rat RG II glioblastoma cells indicated cytotoxic synergy after 48- and 144-hour treatments with PIO and a variety of statins [ 46 ].…”

Section: Statinsmentioning

confidence: 99%

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Skelhorne‐Gross

Nicol

2012

PPAR Research

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Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)γ activation protects against tumourigenesis, results from a few clinical trials using PPARγ ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPARγ ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)α agonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPARγ ligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPARγ ligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPARγ ligands in combination with other agents in the treatment and management of several cancers.

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Section: Statinsmentioning

confidence: 99%

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Skelhorne‐Gross

Nicol

2012

PPAR Research

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“…164 Despite targeting the common transcription factor, combination of lovastatin and thiazolidinediones (PPAR-g agonists) resulted in potentiated cytostatic/cytotoxic effects against various human and murine tumor cells. 165,166 In both reports, the interaction between statin and PPAR-g agonists was strongly synergistic, and observed at lovastatin concentrations as low as 125 nM. 166 Combination of these drugs has not been studied in tumor patients yet, but was already evaluated in clinical trials, being superior to every single drug in terms of improving overall cardiovascular risk profile, reducing cholesterol levels and producing antiinflammatory effects.…”

Section: Combinations With Other Drugsmentioning

confidence: 99%

“…165,166 In both reports, the interaction between statin and PPAR-g agonists was strongly synergistic, and observed at lovastatin concentrations as low as 125 nM. 166 Combination of these drugs has not been studied in tumor patients yet, but was already evaluated in clinical trials, being superior to every single drug in terms of improving overall cardiovascular risk profile, reducing cholesterol levels and producing antiinflammatory effects. [167][168][169] Antitumor activity of butyrate, which is a natural short-chain fatty acid produced by anaerobic fermentation of dietary fibers in the human colon, has been potentiated by statins against human colorectal carcinoma cells 170 and murine colon 171 and lung carcinoma cells.…”

Section: Combinations With Other Drugsmentioning

confidence: 99%

Statins can modulate effectiveness of antitumor therapeutic modalities

Jakóbisiak

Gołąb

2009

Medicinal Research Reviews

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Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed.

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“…Indeed, a synergistic effect was observed on the suppression of cancer cell proliferation through the combination treatment of such drugs. 35 , 36 Also, statin has been reported to activate PPARγ receptor in immune cells. 37 , 38 However, the effects of combined treatment of these drugs in PaSCs have been not yet been fully evaluated.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells

Lee¹,

Lee²,

Kim³

et al. 2012

Gut Liver

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Background/AimsHydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARγ agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression.MethodsPrimary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis.ResultsSimvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF.ConclusionsSimvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.

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Ciglitazone, an agonist of peroxisome proliferator-activated receptor γ, exerts potentiated cytostatic/cytotoxic effects against tumor cells when combined with lovastatin

Cited by 6 publications

References 38 publications

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Statins can modulate effectiveness of antitumor therapeutic modalities

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells

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