Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases

Koutsilieris, Michael; Mitsiades, Constantine S.; Bogdanos, John; Dimopoulos, Theodoros; Karamanolakis, Dimitrios; Milathianakis, Constantine; Tsintavis, A

doi:10.1158/1078-0432.ccr-04-0077

Cited by 42 publications

(31 citation statements)

References 36 publications

(29 reference statements)

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“…combining sms with other drugs, aiming at suppressing the bioavailability of IGF-1 and downstream biological effectors. A potential mechanism for the efficacy of this combination regimen involves the abrogation of the protective effect of IGF-I on prostate cancer cells (14,15). Activation of phosphotyrosine phosphatases (PTPs) by somatostatin receptors (SSTRs) represents one of the main intracellular mechanisms involved in the antiproliferative effect of sms analogues (16).…”

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confidence: 99%

Comparison of protein expression in two prostate cancer cell-lines, LNCaP and DU145, after treatment with somatostatin

Liu

Márquez²,

Nilsson³

et al. 2009

Oncol Rep

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Abstract. The mechanisms underlying prostate cancer progression are poorly understood. Proteins responsive to androgens may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-ablation therapy. Therapy with somatostatin (sms) analogues could be a possible therapeutic alternative to chemotherapy in hormone refractory prostate cancer patients. We used two prostate cancer cell-lines, LNCaP (androgendependent) and DU145 (androgen-independent), to compare the protein expressions. Both cell lines were treated with sms and its derivative smsdx. Smsdx is a glycosylated poly sms with high stability suitable for clinical use. A comparison study of protein expression was analyzed by means of twodimensional gel electrophoresis (2DE) followed by mass spectrometric analysis. Marked quantitative differences were observed in the protein expression profiles in sms/smsdx treated LNCaP and DU145 cells compared to the control cells. One third of the detected proteins were differentially expressed (PRDXs, hnRNPs, HSPs, RKIP). Concordance in protein expression patterns was observed between smsdx and sms treated cells with strong agreement between the up-and down-regulation of proteins. Fifty-eight (isoforms of 49 proteins) protein spots were identified and found differentially expressed at 2-fold change between LNCaP and DU145 cells. Thirty-one proteins in LNCaP have higher expressions than in DU145. Twenty-seven proteins in DU145 have higher expressions than in LNCaP. Most of the differentially expressed proteins (2-fold) between LNCaP and DU145 cells were affected by sms/smsdx treatment (1.2-to 2.6-fold change). Sms/smsdx affects the mitochondria of prostate cancer cells in a way that eventually triggers mitochondrialmediated apoptosis. Regulation of certain proteins (e.g., RKIP, VDACs) by sms/smsdx suggests that sms/smsdx exerts its effects on prostate cancer cells via MAPK pathway and by regulating the activities of phosphotyrosine phosphatases. IntroductionProstate cancer is the most common malignancy and the second leading cause of cancer-related mortality in men in the Western world (1). Although androgen ablation is the most effective therapy for patients with advanced prostate cancer, progression to androgen independence (AIPC) and hormone refractory (HRPC) eventually occurs (2). Androgenindependent prostate cancer carries a bleak prognosis with short survival time. AIPC metastasizes preferentially to the skeleton which is associated with considerable morbidity such as pain and fractures.Several pathways provide insights into the mechanism of androgen action and schemes by which cancer cells subvert normal growth control and escape treatment attempts. Understanding the pathways that lead to AIPC will eventually lead to the development of new therapies. In our previous studies (3,4), smsdx (glycosylated poly sms with high stability suitable for clinical use) was found to be able to trigger upregulation of catalytic mitochondrial proteins and seemed to affect apoptotic-related...

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confidence: 99%

Comparison of protein expression in two prostate cancer cell-lines, LNCaP and DU145, after treatment with somatostatin

Liu

Márquez²,

Nilsson³

et al. 2009

Oncol Rep

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“…The cause of androgen refractoriness and chemotherapy resistance is explained by different molecular processes which involve either genetic alterations present in specific cancer cell clones seeded into bones and/or non-genetic events, such as the role of bone metastasis microenviromentrelated growth factors which are activated locally (10,(48)(49)(50). In a bone metastasis microenvironment, the most important local mediators for the development of chemotherapy resistance and androgen ablation refractoriness involve bone morphogenetic proteins (BMPs), heparin-binding fibroblast growth factor (bFGFs), IGFs, TGFβ1, IL-6, PTHrP, and ET-1, which are all able to act as survival factors, thus inhibiting chemotherapyinduced apoptosis (5,10,(44)(45)(46)(47)(48)(49)(50). In a bone metastasis microenvironment of prostate cancer cell metastasis, locally activated stimuli can activate mitogenactivated protein kinases (MAPKs), especially ERK1/2 and AKT/NFκB/Bcl-2 (11-13,51).…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Attenuates Insulin-Like Growth Factor 1 Receptor Survival Signaling in PC-3 Cells

Papageorgiou

Pitulis

Manoussakis

et al. 2008

Mol Med

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PPARγ, a member of the peroxisome proliferator-activated receptor family, is overexpressed in prostate cancer. Natural and synthetic ligands of PPARγ via genomic and nongenomic actions promote cell cycle arrest and apoptosis of several prostate cancer cells, in vitro. Insulin-like growth factor 1 (IGF-1) inhibits the adriamycin-induced apoptosis of PC-3 human prostate cancer cells. Therefore, we have analyzed the ability of two PPARγ ligands,15dPGJ2 and rosiglitazone, a natural and a synthetic PPARγ ligand, respectively, to increase the adriamycin-induced cytotoxicity of PC-3 cells and to suppress the IGF-1 survival effect on adriamycin-induced apoptosis of PC-3 cells. Our data revealed that both the PPARγ ligands increased the adriamycin-induced cytostasis of PC-3 cells, however, only rosiglitazone added to the adriamycin-induced apoptosis of PC-3 cells. In addition, rosiglitazone attenuated the type I IGF receptor (IGF-1R) survival signaling on adriamycin-induced apoptosis of PC-3 cells via its nongenomic action on ERK1/2 and AKT phosphorylation. Because the IGF-1R signaling is probably the most important host tissue (bone) metastasis microenvironment-related survival signaling for prostate cancer cells, we conclude that rosiglitazone effects on IGF-1R-mediated activation of ERK1/2 and AKT could have clinical implications for the management of androgen ablationrefractory and chemotherapy-resistant advanced prostate cancer with bone metastasis.

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“…To our knowledge, there are no data with respect to the PSA response rate after the use of dexamethasone on this schedule (4 mg every day ϫ 4, weekly). Glucocorticoids have been extensively studied in AIPC as single agents in relatively small Phase II trials, 29 -31 as important (and often overlooked) agents, in combination with other agents, including those that inhibit adrenal steroidogenesis (ketoconazole) [32][33][34] and as the control arm in trials of cytotoxic agents. 36 -38 There are few, if any, data that have established the PSA response rate of various glucocorticoids preparations and schedules.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of high‐dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen‐independent prostate cancer

Trump

Potter

Muindi

et al. 2006

Cancer

101

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The spontaneous recessive mutant mouse stargazer has a specific and pronounced deficit in brain‐derived neurotrophic factor (BDNF) mRNA expression in the cerebellum. Cerebellar granule cells, in particular, show a selective and near‐total loss of BDNF. The mutation involves a defect in the calcium channel subunit Cacng2. This severely reduces expression of stargazin. A stargazin‐induced failure in BDNF expression is thought to underlie the cerebellar ataxia with which the mutant presents. BDNF is known to regulate plasticity at cerebellar synapses. However, relatively little is known about the mechanism involved. We previously demonstrated that the stargazer mutation affects the phenotype of cerebellar glutamatergic neurons. Stargazer neurons have less glutamate and proportionally fewer docked vesicles at presynaptic sites than controls. In the current study, we investigate the mechanism underlying BDNF‐induced synaptic changes by analyzing alterations in synaptic signalling proteins in the stargazer cerebellum. Expression levels of synaptic proteins were evaluated by measuring relative density of immunogold label over granule cell terminals in ultrathin sections from ataxic stargazer mutants compared with matched nonataxic littermates. We show that there is a selective and marked depletion in the levels of vesicle‐associated proteins (synaptobrevin, synaptophysin, synaptotagmin, and Rab3a) but not of plasma membrane‐associated protein (SNAP‐25) in the terminals of the BDNF‐deficient granule cells. Changes are restricted to the cerebellum; levels in the hippocampus are unaltered. These data suggest that the BDNF deficits in the cerebellum of stargazer affect synaptic vesicle docking by selectively altering synaptic‐protein distribution and abundance. J. Comp. Neurol. 512:52–73, 2009. © 2008 Wiley‐Liss, Inc.

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Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases

Cited by 42 publications

References 36 publications

Comparison of protein expression in two prostate cancer cell-lines, LNCaP and DU145, after treatment with somatostatin

Comparison of protein expression in two prostate cancer cell-lines, LNCaP and DU145, after treatment with somatostatin

Rosiglitazone Attenuates Insulin-Like Growth Factor 1 Receptor Survival Signaling in PC-3 Cells

Phase II trial of high‐dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen‐independent prostate cancer

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