Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers

Yokoyama, Yoshihiko; Xin, Bing; Shigeto, Tatsuhiko; Mizunuma, Hideki

doi:10.1007/s00432-011-0993-1

Cited by 38 publications

(24 citation statements)

References 33 publications

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“…For example, weight gain or bone fractures observed in response to administration of PPARγ agonists 187–190, 206 might be offset by agonist activity for PPARα or PPARβ/δ, which can increase lipid catabolism and stimulate osteoblast activity in bone 208 . As there is also good evidence that combining PPAR activation with other chemopreventive or chemotherapeutic agents can significantly increase anti-cancer activities 92, 209–220 , it remains possible that dual or pan PPAR agonists could lead to even greater improvement in efficacy.…”

Section: Ppars and Cancer Treatment And Preventionmentioning

confidence: 99%

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

2012

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

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Section: Ppars and Cancer Treatment And Preventionmentioning

confidence: 99%

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

2012

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“…Further investigation indicated that PPARγ hypermethylation is likely to confer low expression of PPARγ, and hydralazine can cause re-expression of PPARγ by demethylation in triple-negative breast cancer cells. The first report by Yokoyama et al [31] suggested that the combination of ciglitazone and cisplatin leads to synergistic inhibition of the growth of human ovarian cancer by reducing angiogenesis and inducing apoptosis through inhibiting prostaglandin E2 activation via suppressing cyclooxy-genase-2 (Cox-2) expression. In addition, the combination of these 2 compounds does not increase PPARγ activation, which suggests that the main anticancer mechanism of the combination treatment is independent of PPARγ.…”

Section: Combined Treatment With Pparγ Ligandsmentioning

confidence: 99%

PPARγ against Tumors by Different Signaling Pathways

Zhang

Xü

et al. 2013

Oncol Res Treat

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The peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the nuclear hormone receptor superfamily, and is expressed in adipose tissue, skeletal muscle, spleen, heart, liver, placenta, lung, and ovary. PPARγ is a critical regulator of inflammation, adipocyte differentiation, glucose homeostasis, and tumorigenesis. The mechanism of PPARγ on tumor suppression is still unclear, but plenty of evidence shows that PPARγ provides new therapeutic targets for cancer. Here we give a review of how PPARγ and its ligands regulate tumorigenesis by different pathways.

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“…FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9,10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3,12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15).…”

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confidence: 99%

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Wilk

Wyczechowska

Zapata

et al. 2015

Molecular and Cellular Biology

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e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...

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Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers

Cited by 38 publications

References 33 publications

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

PPARγ against Tumors by Different Signaling Pathways

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

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Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers

Cited by 38 publications

References 33 publications

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

PPAR&#947; against Tumors by Different Signaling Pathways

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

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Product

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PPARγ against Tumors by Different Signaling Pathways