Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPAR?-independent mechanism

Artwohl, Michaela; Fürnsinn, Clemens; Waldhäusl, W.; Hölzenbein, Thomas; Rainer, Georg; Freudenthaler, Angelika; Roden, Michael; Baumgartner‐Parzer, Sabina

doi:10.1007/s00125-005-1672-z

Cited by 32 publications

(31 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3a) and has previously been shown to induce G1/S phase arrest in a variety of cell lines, we aimed to determine whether co-treatment with a drug that arrested cells at the G2/M phase would potentiate the anti-tumour effects of rosiglitazone in breast cancer cells (Artwohl et al 2005, Gruszka et al 2005, Sheu et al 2006. As can be seen in Fig.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

Mody

Dharker²,

Bloomston³

et al. 2007

Endocr Relat Cancer

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor-g (PPARg) is a member of the nuclear hormone superfamily and has multiple endogenous and pharmacological ligands, including 15-deoxy-D 12,14 -prostaglandin J 2 and two thiazolidinediones (TZD), rosiglitazone and pioglitazone, which are used clinically to treat type-2 diabetes mellitus. PPARg agonists regulate development, cellular growth and metabolism in various tissues and have been documented to decrease cellular proliferation and to induce apoptosis of various tumour phenotypes, including breast cancer. However, the full spectrum of anti-tumour effects occurs only at suprapharmacological doses. In this study, we investigated the mechanism of rosiglitazone-induced anti-tumour effects of MDA-MB-231 human breast cancer cells, and used that information to predict rosiglitazone-induced sensitization of breast cancer cells to the effects of other compounds. We first confirmed that 100 mM rosiglitazone, but not lower doses, decreases MDA-MB-231 cell viability in vitro. We then used microarray gene expression analysis to determine early rosiglitazone-induced gene expression changes after 4-h exposure, which included 1298 genes that we grouped into functional categories. We selectively confirmed rosiglitazonemediated effects on expression of key regulators of breast cancer proliferation and apoptosis, including p53, p21 and Bax. Finally, we used this information to predict that rosiglitazone would sensitize MDA-MB-231 cells to the anti-tumour effects of CH11, which trimerizes Fas, as well as tumour necrosis factor-a. Moreover, we used the confirmed array data to predict cooperative activity of rosiglitazone and R-roscovitine (CYC202), an inhibitor of multiple cyclin-dependent kinases. We conclude that microarray analysis can determine early TZD-modulated changes in gene expression that help to predict effective in vitro drug combinations.

show abstract

Section: Discussionmentioning

confidence: 99%

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

Mody

Dharker²,

Bloomston³

et al. 2007

Endocr Relat Cancer

View full text Add to dashboard Cite

show abstract

“…HUVECs, HAECs, and HRECs were isolated, cultured, and identified as described (3,(18)(19)(20) and used in the 1st, 5th, and 2nd subcultures, respectively.…”

Section: Endothelial Cell Culturementioning

confidence: 99%

“…Associated protein expression was determined by Western blot analyses as described (3,19) in growing HUVECs with/without FFAs after 24 h exposure. In brief, endothelial cells were lysed in cold Weinberg buffer (3,19) and total protein was measured using a BCA protein assay (Pierce; Rockford, IL) according the manufacturerʼs instructions.…”

Section: Protein Expressionmentioning

confidence: 99%

“…In brief, endothelial cells were lysed in cold Weinberg buffer (3,19) and total protein was measured using a BCA protein assay (Pierce; Rockford, IL) according the manufacturerʼs instructions. An aliquot containing exactly 10 mg total protein was loaded in each lane and subsequently subjected to SDS-PAGE, followed by transfer onto nitrocellulose membranes (Schleicher and Schüll; Kassel, Germany).…”

Section: Protein Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Artwohl

Lindenmair

Sexl

et al. 2008

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Consequently, thiazolidinediones have both PPAR-dependent and -independent mechanisms of action. Troglitazone has been described among others to inhibit endothelial cell proliferation (33) and fibrinolysis proteins (34) and to possess anti-inflammatory properties (35). The PPAR agonist rosiglitazone has been described to ameliorate cisplatin-induced renal injury in mice (36).…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

Vascular damage in testicular cancer patients: A study on endothelial activation by bleomycin and cisplatin in vitro

Meijer¹

2009

Oncol Rep

View full text Add to dashboard Cite

Abstract. Following treatment with bleomycin-and cisplatincontaining chemotherapy, testicular cancer patients frequently develop vascular complications, which may result from damage to endothelial cells. Understanding bleomycin-and cisplatininduced endothelial alterations may help to develop strategies to prevent or reduce vascular toxicity. The effects of bleomycin and cisplatin on proliferation and apoptosis of the human dermal microvascular endothelial cell line HMEC-1 were determined. In addition, modulation of drug-induced cytotoxicity by the free radical scavenger amifostine, the low molecular weight heparin dalteparin, the iron-chelator dexrazoxane, the HMG-CoA reductase inhibitor rosuvastatin and the PPAR agonist troglitazone was tested. Furthermore, the effects of bleomycin and cisplatin on endothelial activation measured by the expression of the intercellular adhesion molecule-1 (ICAM-1) and on two main proteins involved in fibrinolysis, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1), were measured. Decreased endothelial cell survival induced by bleomycin and cisplatin coincided with the induction of apoptosis. Only troglitazone was able to protect the endothelial cells from both bleomycin-and cisplatin-induced cytotoxicity. At high concentrations, amifostine and dexrazoxane also protected HMEC-1 from drug-induced cytotoxicity. However, due to the required high (toxic) concentrations of both modulators no absolute cell survival benefit could be achieved. Both bleomycin and cisplatin induced up-regulation of ICAM-1, tPA and PAI-1. Summarizing, bleomycin and cisplatin induce alterations in the function of endothelial cells regarding proliferation, inflammation and fibrinolysis in vitro. Strategies aimed at these functions should be developed in order to ameliorate or prevent cytostatic agent-induced vascular damage.

show abstract

Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPAR?-independent mechanism

Abstract: In conclusion, this study suggests that the antiproliferative action of the TZDs in vascular cells is independent of their PPARgamma-activating and associated insulin-sensitising potential, but could relate to mitochondrial mechanisms.

Cited by 32 publications

References 49 publications

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-α, CH11 and CYC202

Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells

Vascular damage in testicular cancer patients: A study on endothelial activation by bleomycin and cisplatin in vitro

Contact Info

Product

Resources

About