2-Chloroadenosine modulates PAR-1 and IL-23 expression and enhances docetaxel effects on PC3 cells (original) (raw)
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Biochemical and Biophysical Research Communications, 2003
Therapeutic resistance remains an unresolved problem in the clinical management of human prostate cancer (PC). Despite initial positive response to androgen ablation therapy (AAT), virtually all PC patients will relapse due to acquisition of hormone refractory disease and selective outgrowth of tumor cells with multidrug resistance phenotype. We here provide the first experimental evidence that restoring a functional androgen receptor (AR) in the androgen-independent prostate cancer PC3 cells enhances their sensitivity to growth arrest and suppresses their colony-forming ability in response to paclitaxel and c-irradiation. Furthermore, functional AR increases the susceptibility of these cells to the apoptotic potentials of therapeutic agents, as evidenced by an increase in caspase activity, annexin V binding, and internucleosomal DNA fragmentation, by inducing caspase activation. The abrogation of the cytotoxic effects by 4-hydroxyflutamide suggests a crucial role for AR activation in enhancing the therapeutic sensitivity of these cells in a ligand-independent fashion. Our data thus demonstrate that a functional AR is a prerequisite for effective therapeutic response and that aberrant expression or blockade by AAT may trigger pathways leading to emergence of PC cells with therapeutic resistance phenotype. Since the mainstay of primary therapy for PC has been AAT by pharmaco-therapeutic or surgical means, this study thus provides a new frontier for revising the AAT therapeutic strategy in conjunction with radiation and/or chemotherapeutic agents.
Cancer Research, 2006
Prostate cancer cells are dependent on androgen for growth and survival; as such, inhibition of androgen receptor (AR) activity is the first line of intervention for disseminated disease. Recently, specific cytotoxic agents have been shown to extend survival times in patients with advanced disease. Given the established ability of androgen to modify cell survival in prostate cancer cells, it is imperative to determine the effect of the hormonal environment on cytotoxic response. Here, we show that the response of prostate cancer cells to taxaneinduced cell death is significantly enhanced by androgen stimulation in AR-positive, androgen-dependent prostate cancer cells. Similar results were observed on androgenindependent AR activation. By contrast, AR-positive yet androgen-independent or AR-negative cells were refractory to androgen influence on taxane function. The ability of androgen to potentiate taxane activity was dependent on its mitogenic capacity and was separable from overall AR activity, as coadministration of AR antagonists, G 1 cyclin-dependent kinase inhibitors, or high-dose (growth inhibitory) androgen nullified the proapoptotic function of androgen. Observed induction of cell death was attributed to caspase-dependent apoptosis and correlated with p53 activation. Combined, these data indicate that the cytotoxic effects of taxanes are substantially influenced by the hormonal environment and/or status of AR activity in prostate cancer cells and provide the foundation for refinement and optimization of cytotoxic intervention in prostate cancer. (Cancer Res 2006; 66(24): 11998-2008)
Acta Oncologica, 2005
Once bone metastasized and androgen independent, prostate cancer is often associated with skeletal morbidity and disability. New treatment modalities that can palliate symptoms from the skeleton and inhibit further progression are warranted. In this study, the antitumoral effects following treatment with a combination of docetaxel and the new generation bisphosphonate, zoledronic acid, were investigated on two hormone-refractory prostate cancer cell lines: PC3 and DU145. The prostate cancer cells were treated with increasing concentrations of zoledronic acid in the absence or presence of docetaxel. Toxicity was measured using fluorometric microculture cytotoxic assay technique. A concentration of 25 mM, zoledronic acid reduced the viable cell number to 68% and 98% for PC3 and DU145 cells respectively. Docetaxel, on the other hand, at a concentration of 0.1 ng/ml, had no effect on the viability. However, a combination of zoledronic acid and docetaxel reduced the cell number to 60% and 81% respectively. Furthermore, zoledronic acid in the concentration range 12.5 mM Á/50 mM enhanced the antitumoral effects of docetaxel (0.01 Á/1 ng/ml) in an additive and/or synergistic manner for both cell lines. These data support the hypothesis that zoledronic acid, in addition to having bone resorption inhibiting properties, also exhibits anti-tumoral effects. It also appears that combined treatment with docetaxel causes additive and/or synergistic cytostatic effects on prostate cancer cells.
Androgen Independent Human Prostate Cancer Cell Line, PC3
Journal of Surface Science and Technology
The commercially available long acting anti-asthmatic drug, formoterol exists as a racemate of four enantiomers ((R,R)-, (R,S)-, (S,R)-and (S,S)-. The study describes several comparisons between two completely different enantiomers, (R,R)-and (S,S)-based on their # 1) cell surface binding, # 2) cAMP elevation ability, # 3) G-protein activation and # 4) inhibition of DNA synthesis in PC3 cells. The presence of high affinity 2-adrenergic receptor (K d 3 0 pmol/L) was confirmed by competition binding of 125 I-cyanopindolol with increasing concentration of (R,R)-formoterol using both intact PC3 cells and isolated plasma membrane. Replacing (R,R)-by (S,S)-yielded no significant binding interaction proving its ineffectiveness toward the 2-adreno-receptor. While both were capable of eliciting prolonged cAMP generating activity in intact PC3 cells, the EC 50 values (R,R-= 10.5 pM, R,S-= 11.0 pM and S,S = 1000 pM) varied nearly 100 fold in favor of (R,R)-and (R,S)-. Propanolol effectively inhibited cAMP elevation in intact cells in both the cases as also agonist stimulated incorporation of [ 32 P]-GTP-AA (Guanosine triphosphate azidoanilide) by (R,R)-in isolated PC3 membrane, but failed in both events in the presence of (S,S)-enantiomer although incorporation of [ 32 P]-GTP-AA is specific for both the enantiomers. The unique discriminatory behavior is further observed in presence of muscarinic agonist, carbachol, which potentiated cAMP generation by (R,R)-nearly 2-3 fold, but was unable to do so in the presence of (S,S)-. These facts confirmatively indicate that cAMP elevation by (S,S)-in PC3 cells occurs entirely via a different pathway than its (R,R)counterpart. Interestingly, both enantiomers can effectively lower the DNA synthesis, showing superior efficacy of (R,R)- .
Modern approaches for antiandrogen-resistant prostate cancer therapy
Journal of Mind and Medical Sciences, 2021
Prostate cancer represents the leading malignant tumor in men over 50 years of age with 400,000 new cases being diagnosed yearly in Europe. Even if the incidence rate is higher than the mortality rate, still there is an increasing trend when speaking of its mortality. The increasing incidence of the metabolic syndrome, the unhealthy lifestyle, the high lipid and Calcium intake, the high spread of infections with Human Papilloma Virus, Human Herpes Virus, the excess of androgen consumption and the longer life expectancy, are few of the main causes of prostate cancer increasing incidence. The new systemic therapies such as immunotherapy with Checkpoint Inhibitors or Poly, ADP-Ribose Polymerase inhibitors and local experimental procedures addressing tumor destruction, such as High- Intensity Focused Ultrasound, the Cryo and Focal Laser Ablation, provide good outcomes and become new promising tools for prostate cancer therapy. Physicians consider these methods worth using; the efficacy ...
Cancer Research, 2009
Androgen receptor (AR) is known to be overexpressed in castration-resistant prostate cancer. To interrogate the functional significance of the AR level, we established two LNCaP cell sublines expressing in a stable fashion two to four times (LNCaP-ARmo) and four to six times (LNCaP-ARhi) higher level of AR than the parental cell line expressing the empty vector (LNCaP-pcDNA3.1). LNCaP-ARhi cell line grew faster than the control line in low concentrations, especially in 1 nmol/L 5A-dihydrotestosterone (DHT). Microarray-based transcript profiling and subsequent unsupervised hierarchical clustering showed that LNCaP-ARhi cells clustered together with VCaP cells, containing endogenous AR gene amplification and overexpression, indicating the central role of AR in the overall regulation of gene expression in prostate cancer cells. Two hundred forty genes showed >2-fold changes on DHT treatment in LNCaP-ARhi at 4 h time point, whereas only 164 and 52 showed changes in LNCaP-ARmo and LNCaP-pcDNA3.1, respectively. Many androgen-regulated genes were upregulated in LNCaP-ARhi at 10-fold lower concentration of DHT than in control cells. DHT (1 nmol/L) increased expression of several cell cycle-associated genes in LNCaP-ARhi cells. ChIP-on-chip assay revealed the presence of chromatin binding sites for AR within F200 kb of most of these genes. The growth of LNCaP-ARhi cells was also highly sensitive to cyclin-dependent kinase inhibitor, roscovitine, at 1 nmol/L DHT. In conclusion, our results show that overexpression of AR sensitizes castration-resistant prostate cancer cells to the low levels of androgens. The activity of AR signaling pathway is regulated by the levels of both ligand and the receptor. [Cancer Res 2009;69(20):8141-9]
Androgen receptors in prostate cancer
Endocrine Related Cancer, 2002
The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, res...
The Journal of Urology, 2003
Purpose: Prostate cancer is known to be refractory to chemotherapy with only mitoxantrone showing some benefit. Recent clinical data indicate the antitumoral efficacy of taxanes alone or combined with estramustine phosphate. We compared the response to these treatments of hormone dependent and independent human prostate cancer xenografts. Materials and Methods: PAC120, an androgen dependent human prostate cancer xenograft, and several HIDs, which are androgen independent variants, were established in nude mice. Human gene expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Androgen deprivation was achieved by surgical castration. Tumor bearing mice received 20 mg./kg. docetaxel on day 2, 1 mg./kg. hydrocortisone on days 1 to 3, 4 mg./kg. estramustine phosphate on days 1 to 4 or 1 mg./kg. mitoxantrone on day 1 by the intraperitoneal route for 3-week cycles. Relative tumor volume and growth delay were evaluated. Histological examination of tumors was done before and after treatment. Results: Mitoxantrone transiently decreased the growth rate of HID xenografts but did not affect that of PAC120. Estramustine phosphate alone inhibited the growth of PAC120 but not that of HID variants. Docetaxel inhibited the growth of all prostate cancer xenografts (PAC120 and HIDs) and increased survival. PAC120 showed distinct response patterns during prolonged treatment. Efficacy was significantly decreased by splitting docetaxel into 2 doses given at a 7-day interval (p ϭ 0.01). The docetaxel effect was potentiated by estramustine phosphate in 1 of the 2 HID variants tested. In castrated mice docetaxel induced a greater growth delay than in intact male mice (p ϭ 0.01). High Her2/neu and 2-tubulin transcripts were detected in all samples. Prostate specific antigen, androgen receptor and multidrug related protein-1 mRNA did not correlate with the drug response, while CYP3A4 mRNA inversely correlated with the response. Docetaxel treated tumors had an increased number of mitotic cells with centrosome alterations and multinuclei, an increased number of Ki67 labeled cells and a strong decrease in -tubulin without evidence of apoptosis. Conclusions: Docetaxel showed a significant antitumoral effect on hormone dependent and tumors, which was largely superior to that of mitoxantrone. Estramustine phosphate alone had a modest effect. The drug response was associated with high Her2/neu expression, low CYP3A4 expression and the induction of numerous mitotic abnormalities.
Androgens Induce Resistance to bcl-2-mediated Apoptosis in LNCaP Prostate Cancer Cells
Cancer Research, 1995
We describean in vitro model for prostatecancer treatment that suggests a potential benefit for combIned androgen ablation and cytotoxlc chemotherapy. Androgen freatment of the LNCaP hormone-dependent human prostate cancer cell line Induces Increased expression ofthe BCL-2 protein. Increased levels ofthis protein are known to mediate inhibition of apoptosis.LNCaP cells,however,did not undergoapoptosisin responseto androgen withdrawaL Etoposide exerts its Cytotoxicity on LNCaP and other cells by inducingapoptosis. In vitro etoposidecytotoxicitywas diminished 83% In the presence of either iO@ M dlhydrotestosteroae or io-9 MRiSSiin LNCaP cells. TheInteraction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxidty. Received12/6/94;accepted1/6/95. The costsof publicationof this article were defrayedin part by the paymentof page charges.This article must thereforebe hereby marked advertisementin accordancewith 18 U.S.C.Section1734solelyto indicatethisfact. 1 Supported by National Cancer Institute Grant CA57176, an award from the CAPCure Foundation, and fellowships from InstitutJulesBordet(Brussels, Belgium)and the Ministry of Education of the Grand Duchy of Luxemburg to 0. B.