Glucocorticoids Suppress Tumor Angiogenesis and <i>In vivo</i> Growth of Prostate Cancer Cells

Yano, Akihiro; Fujii, Yasuhisa; Iwai, Aki; Kageyama, Yukio; Kihara, Kazunori

doi:10.1158/1078-0432.ccr-05-2085

Cited by 131 publications

(122 citation statements)

References 32 publications

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“…Recent reports have shown that several natural peptides, including thyroid hormones, are able to inhibit cancer cell proliferation , Saji et al 2005, Vesely 2005, Yano et al 2006. In the present study, we have demonstrated that T 3 hormone exposure exerts an anti-proliferative effect on human ductal pancreatic adenocarcinoma cell growth, and that it is able to increase the effect of dFdCyd and DDP acting synergistically with them.…”

Section: Discussionsupporting

confidence: 62%

3,3′,5-Triiodo-l-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy

Michienzi

Bucci

Falzacappa

et al. 2007

Journal of Endocrinology

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The pancreatic adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression, and profound resistance to actual treatments, including chemotherapy and radiotherapy. At the moment, surgical resection provides the best possibility for long-term survival, but is feasible only in the minority of patients, when advanced disease chemotherapy is considered, although the effects are modest. Several studies have shown that thyroid hormone, 3,3 0 ,5-triiodo-L-thyronine (T 3 ) is able to promote or inhibit cell proliferation in a cell type-dependent manner. The aim of the present study is to investigate the ability of T 3 to reduce the cell growth of the human pancreatic duct cell lines chosen, and to increase the effect of chemotherapeutic drugs at conventional concentrations. Three human cell lines hPANC-1, Capan1, and HPAC have been used as experimental models to investigate the T 3 effects on pancreatic adenocarcinoma cell proliferation. The hPANC-1 and Capan1 cell proliferation was significantly reduced, while the hormone treatment was ineffective for HPAC cells. The T 3 -dependent cell growth inhibition was also confirmed by fluorescent activated cell sorting analysis and by cell cycle-related molecule analysis. A synergic effect of T 3 and chemotherapy was demonstrated by cell kinetic experiments performed at different times and by the traditional isobologram method. We have showed that thyroid hormone T 3 and its combination with low doses of gemcitabine (dFdCyd) and cisplatin (DDP) is able to potentiate the cytotoxic action of these chemotherapic drugs. Treatment with 5-fluorouracil was, instead, largely ineffective. In conclusion, our data support the hypothesis that T 3 and its combination with dFdCyd and DDP may act in a synergic way on adenopancreatic ductal cells.

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Section: Discussionsupporting

confidence: 62%

3,3′,5-Triiodo-l-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy

Michienzi

Bucci

Falzacappa

et al. 2007

Journal of Endocrinology

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“…This discovery is very important in revealing the molecular mechanism on the tumor suppressing function of 15-LOX-2 gene. This is because glucocorticoid hormones are known to regulate proliferative, inflammatory and immune responses via its receptors GR (14)(15)(16)(17). Clinically, glucocorticoid hormones, combined with or without chemotherapy, have been extensively used for the treatment of hormone refractory prostate cancer (HRPC).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells

Feng

Bai²,

Yang³

et al. 2010

Int J Oncol

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Abstract. 15-lipoxygenase 2 (15-LOX-2) is lost or significantly reduced in prostate cancer. However, the regulation of 15-LOX-2 remains unclear. In this study, we independently cloned the 5' upstream promoter fragments of 15-LOX-2 gene. Target DNA fragments each were cloned into an expression vector containing luciferase reporter gene, which were called LF1(-1533/+87), LF2(-628/+87), LF3(-253/+87), LF4(-157/ +87), LF5(-33/+87), LF6(-253/+1), and LF7(-157/+1). Each of these individual promoter fragments was transfected into primary prostate epithelial cells and prostate cancer LNCaP cells. The promoter activity gradually decreased with progressive deletions from LF2 to LF4. A significant drop was noted in the LF5. LF6 and LF7 that did not contain the 87-bp region downstream the transcription start site (TSS) have significant luciferase activities similar to those of corresponding fragments (LF3 and LF4) that contain 87-bp region downstream the TSS. This suggests that the 125-bp region (-157 to -33) of LF4 is critical for the promoter activity of 15-LOX-2 in the primary prostate epithelial cells PrEC and cancer cells LNCaP. Moreover, we discovered a specific glucocorticoid receptor (GR) responsive element (GRE) in this key region. The luciferase activities of the LF4 and LF7 were decreased in the LNCaP cells co-transfected with GR (hGR· or hGRß) expression vectors. This inhibitory effect is reversed after treatments with dexamethasone or two specific GR inhibitors (siRNAs of GR and RU486). Results from this study suggest a 125-bp region (-157 to -33) is critical for the 15-LOX-2 promoter activity in prostate epithelial cells and cancer cells, which was significantly downregulated by GR via the GRE in this region.

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“…Dexamethasone has been shown to suppress proangiogenic gene transcription and secretion in a range of CRPC cells in vitro, whereas a subcutaneous administration of DEX inhibits tumour growth and angiogenesis in an in vivo DU145 xenograft model of CRPC (Yano et al, 2006). The impact of co-administering DEX on the antiangiogenic activity of docetaxel was initially studied using an in vitro assay that measures the capacity of endothelial cells to promote vessel development in a co-culture system.…”

Section: Discussionmentioning

confidence: 99%

“…Glucocorticoids have been shown to interfere with the transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) (Nishimura et al, 2001), resulting in the suppression of the interleukin-6 (IL-6) and the NF-kB-IL-6 pathways in CaP (Akakura et al, 2003;De Bosscher et al, 2003). Dexamethasone has also been shown to inhibit angiogenesis in a CaP xenograft model, reducing cell and tumour IL-8 and VEGF expression in in vitro and in vivo assays, respectively (Yano et al, 2006). CXC-chemokines including IL-8 have an established role in promoting the progression of CaP .…”

mentioning

confidence: 99%

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Wilson¹,

Scullin²,

Worthington³

et al. 2008

Br J Cancer

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We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kB (NF-kB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (Po0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (Po0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

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Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Cited by 131 publications

References 32 publications

3,3′,5-Triiodo-l-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy

3,3′,5-Triiodo-l-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy

Downregulation of 15-lipoxygenase 2 by glucocorticoid receptor in prostate cancer cells

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

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