Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

Zhang, Yanqin; Tang, Xiao‐Qing; Sun, Lan; Dong, Lin; Qin, Yong; Liu, Huaqing; Xia, Hong; Cao, Ji

doi:10.3748/wjg.v13.i10.1534

Cited by 34 publications

(33 citation statements)

References 27 publications

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“…28 We recently observed that downregulation of XIAP greatly enhanced the antitumor effects of troglitazone. Others have recently reported that rosiglitazone could synergisti- cally enhance the antitumor effect of certain anticancer drugs, 16 and promising results have been reported in clinical trials. 29,30 As rosiglitazone is a widely used antidiabetic drug, it would be more clinically relevant to explore the anticancer effect of this agent.…”

Section: Discussionmentioning

confidence: 97%

“…15 A low dose of rosiglitazone ( 30 lM) had no inhibitory effect on HT-29 cell proliferation, but an even lower dose (10 lM) could sensitize HT-29 cells to 5-FUinduced apoptosis. 16 Contradictory to this study, treatment of HT-29 cells with 0-10 lM of rosiglitazone resulted in a dose-and time-dependent inhibition of cell growth and apoptosis. 21 Several recent studies even suggest that rosiglitazone can stimulate the growth of cancer cells.…”

mentioning

confidence: 84%

“…Rosiglitazone has been tested on various cancers including colon cancer [14][15][16][17][18][19][20] with wide effective dose ranges. However, the anticancer effect of rosiglitazone varies considerably in different cancers, and even in the same cancer type, the reported results are variable.…”

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confidence: 99%

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Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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Section: Discussionmentioning

confidence: 97%

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confidence: 84%

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Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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“…Recent evidence has demonstrated that PPARγ activation by TZDs inhibits cell growth and induces cell apoptosis in liver cancer cell lines [24,25] . Moreover, rosiglitazone, as a PPARγ synthetic ligand, has been shown to enhance the antitumor www.chinaphar.com Cao LQ et al Acta Pharmacologica Sinica npg activity of some chemotherapeautic drugs by the modulation of cancer cell agents [26,27] . However, the effects of rosiglitazone on hepatoma cells have been poorly understood until now.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway

Cao

Wang²,

Wang

et al. 2009

Acta Pharmacol Sin

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Aim: Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell lines. In this study, we examine rosiglitazone-induced sensitization of HCC cell lines (BEL-7402 and Huh-7 cells) to 5-FU. Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARγ, PTEN, and COX-2) in BEL-7402 cells. Immunohistochemistry staining was used to examine the expression of PTEN in 100 advanced HCC tissues and paracancerous tissues. In addition, small interfering RNA was used to suppress PPARγ, PTEN, and COX-2 expression. Results: Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARγ signaling pathway. Activation of PPARγ by rosiglitazone increases PTEN expression and decreases COX-2 expression. Since distribution of PTEN in HCC tissues is significantly decreased compared with the paracancerous tissue, over-expression of PTEN by rosiglitazone enhances 5-FU-inhibited cell growth of HCC. Moreover, down-regulation of COX-2 is implicated in the synergistic effect of 5-FU. Conclusion: Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARγ. The results suggest potential novel therapies for the treatment of advanced liver cancer.

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“…Unfortunately, no significant effect could be observed when troglitazone alone was administered in patients with metastatic colorectal cancer included in a phase II clinical trial (46). Recent reports demonstrated a synergy between PPARÁ ligands and current anticancer therapies such as fluorouracil (47), carboplatin (48,49) or tamoxifen (50). Thus, it would be interesting to evaluate the effect of PPARÁ ligand in clinical trials, alone or in combination with other molecules.…”

Section: Discussionmentioning

confidence: 99%

PPARγ is functionally expressed in clear cell renal cell carcinoma

Collet

Théoleyre²,

Rageul³

et al. 2011

Int J Oncol

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Abstract. Peroxisome proliferator-activated receptor gamma (PPARÁ) agonists have been demonstrated to exert an inhibitory effect on cell growth in several tumor models, including clear cell renal cell carcinoma (CCRCC). PPARÁ has therefore been proposed to be a potential therapeutic target. Thus, the PPARÁ gene must be expressed and not altered in cancer cells. We have therefore analyzed tumor specimens collected from 63 patients with CCRCC who underwent partial or total nephrectomy. The multiplex ligation-dependent probe amplification (MLPA) assay was used to detect deletions in the PPARÁ gene. The majority of the tumors (48/63; 76.2%) did not present alterations. Two samples (3.2%) presented a deletion of the non-coding exon A1. Nine samples (14.3%) showed large heterozygous deletions in chromosome 3p including PPARÁ. Potential mutations were analyzed by DNA sequencing of the 6 coding exons of the PPARÁ gene. No mutation was found in exons 1-5. In exon 6, a silent polymorphism was detected in 14 samples (22.2%). CCRCC were found to express the PPARÁ1 isoform. The expression level of PPARÁ was measured by real-time quantitative PCR. A significantly reduced transcript level was associated with an elevated Fuhrman grade. Finally, we analyzed the expression of angiopoietin-like 4, a known PPARÁ target gene, in CCRCC cell lines cultured in the presence of rosiglitazone, a PPARÁ agonist. A strong induction was found in the 3 cell lines tested, indicating that PPARÁ is functional in all these cell lines. In conclusion, we show here that PPARÁ is expressed and functional in CCRCC, prerequisites for being a potential target for CCRCC treatment.

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Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

Cited by 34 publications

References 27 publications

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway

PPARγ is functionally expressed in clear cell renal cell carcinoma

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