Effects of the dual 5 alpha reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells

McCrohan, A.; Coffey, Ronan; Morrissey, Colm; O'Keane, C; Mulligan, Neil W.; Watson, Chanel; Smith, James D.; Fitzpatrick, John M.; William, R.; Watson, G.

doi:10.1016/s1569-9056(03)90489-1

Cited by 9 publications

(10 citation statements)

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“…Recently Mostaghel et al [28] have shown that high dose dutasteride treatments were associated with fewer cancer incidences in patients with specific gene expressions. Although not directly correlating to our study, it showed an increased interest in the anti-neoplastic potential of dutasteride at high dosages [14,15]. Future studies are warranted examining the mechanism of action of these agents at lower concentrations.…”

Section: Metforminmentioning

confidence: 53%

“…Dutasteride was originally demonstrated to reduce benign prostatic hyperplasia, through preventing the conversion of testosterone to the more potent androgen DHT [12]. However, recent studies have shown that dutasteride induces apoptosis in prostate cancer cells through a FASN-mediated pathway [10,[13][14][15]. This newly found potential of dutasteride requires further investigation for this to be considered as a potent therapeutic option for PCa.…”

Section: Introductionmentioning

confidence: 99%

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Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Besla

Venier²,

Colquhoun³

et al. 2013

TOPCANJ

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Prostate cancer (PCa) is the second most prevalent cancer in men after lung cancer. Prostate cancer development and progression is associated with the dysregulation of a number of molecular pathways; hence, therapeutic strategies targeting such pathways bring great promise. Recently we have shown that metformin, the anti-diabetic drug, can inhibit tumor progression when combined with dutasteride, a 5-alpha-reductase inhibitor (5ARI). Interestingly, both metformin and dutasteride have been reported to alter the Sterol Regulatory Element Binding Proteins (SREBP) Fatty Acid Synthase (FASN) pathway. The SREBP pathway is involved with lipid and energy homeostasis. In our present study, we investigated if dutasteride in combination with metformin can reduce the proliferation of LNCaP PCa cells, and whether this is mediated through the SREBP-1/FASN pathway. Human PCa cells were treated with either dutasteride (0-100 µM) or metformin (0-50 mM) alone or in combination. The treated cells were then incubated for up to 24 hours, and proliferation assessed using the MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Western blot analysis was performed on cell lysates to assess alterations in key signaling molecules including cleaved SREBP-1, FASN, AR, PSA, pAMPK and apoptotic markers. Results revealed that there was a significant (p<0.05) decrease in cellular proliferation of LNCaP cells treated with a combination of metformin and dutasteride, this effect being greater than either treatment alone. Treating LNCaP cells with both metformin and dutasteride reduced the expression of FASN, cleaved SREBP-1 and pro-caspase-3 with expression of cleaved PARP; suggesting a possible interaction between FASN and apoptosis. All treatments resulted in reductions in AR, PSA and an upregulation of pAMPK, with the highest expression seen in combination treatment. We report for the first time that metformin and dutasteride in combination can reduce the proliferation of androgen-sensitive cell line through the activation of p-AMPK, and SREBP-1/FASN pathway and highlight the importance of targeting the SREBP-1 pathway, for improving future therapeutic strategies for prostate cancer.

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Section: Metforminmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Besla

Venier²,

Colquhoun³

et al. 2013

TOPCANJ

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“…PC3AR2 cells are PC3 cells transfected with full-length functional AR. 25 Thus, LNCaP and PC3AR2 cells express functional AR, whereas PC3 and DU145 cells do not. Cells were cultured at 37 1C in a 5% CO 2 incubator in the following media: LNCaP cells, RPMI 1640 medium (Invitrogen, Burlington, Ontario, Canada) supplemented with 10% fetal bovine serum (Sigma, St Louis, MO, USA), 0.3 mg ml À1 L-glutamine and 100 IU ml À1 penicillin and 100 mg ml À1 streptomycin (Invitrogen); PC3 and DU145 cells, Dulbecco's minimal essential medium/F12 (Invitrogen) with 10% fetal bovine serum supplemented with 0.3 mg ml À1 L-glutamine and 100 IU ml À1 penicillin and 100 mg ml À1 streptomycin; PC3AR2 cells, RPMI 1640 medium supplemented with 5% fetal bovine serum, 0.3 mg ml À1 L-glutamine, 100 IU ml À1 penicillin and 100 mg ml À1 streptomycin, Fungizone (250 mg ml À1 amphotericin B and 250 mg ml À1 deoxycholate, Invitrogen) and 100 mg ml…”

Section: Cell Linesmentioning

confidence: 97%

Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer

Colquhoun

Venier

Vandersluis

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Prostate cancer incidence and mortality vary dramatically by geographical location. Both are higher in developed countries. Some attribute this to westernized lifestyles of high-energy diets and limited physical activity with consequent obesity. Obesity and obesity-related diseases like diabetes cause hyperinsulinaemia, which upregulates pro-survival cell signalling. Previous work revealed diet-induced hyperinsulinaemia enhances prostate cancer xenograft growth in vivo. Metformin, an antidiabetic medication, reduces hyperinsulinaemia and also exhibits antineoplastic properties. Herein, we assess the potential additive benefit of combining bicalutamide antiandrogen therapy with metformin, in vitro and in vivo. METHODS: Using clonogenic assays, we assessed the effect of bicalutamide and/or metformin on clonogenicity in prostate cancer cell lines. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs in androgen receptor (AR)-positive (LNCaP) and AR-negative (PC3) cell lines. The combination treatment regimen was assessed in vivo using an LNCaP murine xenograft model. RESULTS: Micromolar bicalutamide or millimolar metformin caused a significant dose-dependent reduction in clonogenicity (Po0.001). Combination treatment further significantly reduced clonogenicity (Po0.005) with greater effects in AR-positive cells. Western blot and cell cycle analyses suggested differing mechanisms of interaction in AR-positive and -negative cell lines. Following combination treatment, LNCaP cells exhibited an altered cell proliferation (decreased phospho mammalian target of rapamycin expression) and perturbed cell cycle kinetics (G1/S cell cycle arrest). PC3 cells showed evidence of enhanced apoptosis (increased Bcl-2-associated X protein and decreased total caspase 3 expression). Markedly diminished tumour growth occurred following combination treatment in vivo (Po0.001). CONCLUSIONS: Combining bicalutamide and metformin significantly reduces prostate cancer cell growth further than either monotherapy. In AR-positive cells, this effect appeared to be mediated by reducing proliferation rates, whereas in AR-negative cells the combination treatment appeared to promote apoptosis. This combination drug regimen may improve prostate-cancerspecific survival by the direct antineoplastic properties outlined.

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“…RNA isolation and cDNA synthesis RNA was isolated using Tri-Reagent (Invitrogen, Paisley, UK) as previously described 15 and used to generate cDNA as previously described. 15 PCR amplification of cDNA template was performed in a thermal cycler (Perkin Elmer 7700).…”

Section: Cell Culture Hypoxia Treatments and Triggers Of Apoptosismentioning

confidence: 99%

Hypoxia increases normal prostate epithelial cell resistance to receptor‐mediated apoptosis via AKT activation

Walsh

Gill

O’Neill

et al. 2009

Intl Journal of Cancer

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The aging prostate is associated with changes in its vascular structure, which could lead to changes in oxygen levels. Hypoxia is an important environmental change that leads to the progression of many cancers mediated through a number of cellular changes, which included resistance to apoptosis. The role of hypoxia in initiating tumour development has not been previously investigated. We demonstrate that normal prostate epithelial cells develop a resistance to receptor-mediated apoptosis following 24 hr of 1% hypoxia. This effect is associated with the altered expression of a number of pro-and anti-apoptotic proteins, which leads to inhibition of Cytochrome c release and downstream caspase activation. This is mediated via decreased Bax translocation and upstream Caspase 8 activity. Despite increased expression of cIAP-2, small interfering RNA (siRNA) knockdown does not restore susceptibility to TRAIL-induced apoptosis. Gene expression analysis indicated potential changes in AKT activation, which was confirmed by increased phosphorylation of AKT. Inhibition of this phosphorylation reversed the resistance to TRAIL-induced apoptosis. AKT activation is emerging as a key survival signal in prostate cancer. This study demonstrates that short exposure to low oxygen can increase resistance to immune surveillance mechanisms and might confer a survival advantage onto normal prostate epithelial cells so that they can survive subsequent genomic instability and other carcinogenetic insults leading to the early development of prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: hypoxia; prostate; apoptosis; inhibitor of apoptosis; AKT One of the most significant risk factors for the development of prostate cancer is age. Ageing has been associated with progressive changes of physiological functions with time. One example is the increase in tissue hypoxia of organs such as the kidneys 1 and brain. 2 Additionally, with advancing age, the incidence of ischaemic disease increases, for example, those of acute myocardial infarction and stroke. 3 The prostate is also associated with the development of age-related disease. For instance, benign prostatic hyperplasia (BPH) occurs in 20% of men aged 40 years and in 70% of men aged 60 years. Autopsy studies have shown that men aged between 20 and 29 years show evidence of high-grade prostatic intraepithelial neoplasia (PIN) (7.14%) and foci of prostate cancer (3.14%), which increases in men aged 50-59 years, who have increased incidences of PIN (23.8%) and prostate cancer (38.06%). 4 Although hypoxia is most frequently associated with malignancy, with >70% of prostate cancer displaying upregulated HIF1a, 5 the normal aging prostate is also thought to be associated with an hypoxic environment, with the ageing cardiovascular system leading to an age-associated decline in prostatic blood flow. 6 Additionally, men with clinical cardiovascular disease/atherosclerosis or hypertension are at an increased risk for BPH development. 7 Damage to the vascular region of the prostatic transitional zone...

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Effects of the dual 5 alpha reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells

Cited by 9 publications

References 0 publications

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer

Hypoxia increases normal prostate epithelial cell resistance to receptor‐mediated apoptosis via AKT activation

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