A new dawn for the use of thiazolidinediones in cancer therapy

Joshi, Hardik; Pal, Tanushree; Ramaa, C. S.

doi:10.1517/13543784.2014.884708

Cited by 46 publications

(36 citation statements)

References 56 publications

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“…This novel information may have important implications for the responsiveness of different disease types to treatment with these compounds. The dual action of PPAR agonists may also account for the variable effects of PPAR activation in the treatment and development of distinct tumor entities [36–38]. It is possible that the activation status of the cancer cells or tumor stromal cells, including macrophages, fibroblasts, endothelial cells, and others, may influence PPAR function.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

et al. 2016

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BackgroundPeroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPARα and δ activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPARα and δ agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells.ResultsWe found that PPARα and PPARδ agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPARδ induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPARα failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPARδ, but not PPARα agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPARα and PPARδ agonists increased ICAM-1 mRNA stability.ConclusionTherefore, our data provide the first evidence that PPARα and PPARδ agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.

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Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

et al. 2016

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“…Collectively, this suggests that PPAR activation is involved in the anti‐tumour effects of cannabinoids. In support of this, there is increasing evidence that the thiazolidinedione class of PPARγ ligands, normally used in the treatment of diabetes, may have a potential new role in the treatment of cancer (Joshi et al , ).…”

Section: Physiological Responses To Cannabinoids Mediated By Pparsmentioning

confidence: 97%

An update on PPAR activation by cannabinoids

O’Sullivan

2016

British J Pharmacology

358

251

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Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti‐inflammatory, metabolic, anti‐tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.

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“…Among the synthetic ligands, thiazolidinediones, a class of medications originally used for the treatment of type 2 diabetes mellitus, have been widely investigated as anti–lung cancer agents. The administration of thiazolidinediones for anticancer therapy is known to produce some side effects . Moreover, recent studies have further shown that the prolonged use of thiazolidinediones is associated with an increased risk of bladder cancer .…”

Section: Introductionmentioning

confidence: 99%

“…The administration of thiazolidinediones for anticancer therapy is known to produce some side effects. 16 Moreover, recent studies have further shown that the prolonged use of thiazolidinediones is associated with an increased risk of bladder cancer. 17 These adverse effects have limited the therapeutic application of synthetic PPARc ligands.…”

Section: Introductionmentioning

confidence: 99%

Antineoplastic effects of 15(S)‐hydroxyeicosatetraenoic acid and 13‐S‐hydroxyoctadecadienoic acid in non–small cell lung cancer

et al. 2015

Cancer

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BACKGROUND Previous studies have shown that the levels of 15‐lipoxygenase 1 (15‐LOX‐1) and 15‐LOX‐2 as well as their metabolites 13‐S‐hydroxyoctadecadienoic acid (13(S)‐HODE) and 15(S)‐hydroxyeicosatetraenoic acid (15(S)‐HETE) are significantly reduced in smokers with non–small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen–induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC. METHODS NSCLC cells were treated with exogenous 13(S)‐HODE and 15(S)‐HETE, and then the ways in which they affected cell function were examined. 15‐LOX‐1 and 15‐LOX‐2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)‐HODE and 15(S)‐HETE before cell function was assessed. RESULTS The application of exogenous 13(S)‐HODE and 15(S)‐HETE significantly enhanced the activity of peroxisome proliferator‐activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15‐LOX‐1 and 15‐LOX‐2 obviously promoted the endogenous levels of 13(S)‐HODE and 15(S)‐HETE, which were demonstrated to be more effective in the inhibition of NSCLC. CONCLUSIONS This study has demonstrated that exogenous or endogenous 13(S)‐HODE and 15(S)‐HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15‐LOX activity to increase the production of endogenous 15(S)‐HETE and 13(S)‐HODE may offer a novel research direction for molecular targeting treatment of smoking‐related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands. Cancer 2015;121:3130‐45. © 2015 American Cancer Society.

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A new dawn for the use of thiazolidinediones in cancer therapy

Cited by 46 publications

References 56 publications

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

An update on PPAR activation by cannabinoids

Antineoplastic effects of 15(S)‐hydroxyeicosatetraenoic acid and 13‐S‐hydroxyoctadecadienoic acid in non–small cell lung cancer

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