Effect of Combination therapy of Desmopressin and Docetaxel on prostate cancer cell DU145 proliferation, migration and growth

Background: This study was designed to assess the efficacy of the combination of Desmopressin and Docetaxel for prostate cancer. Desmopressin has been demonstrated to inhibit tumor progression and metastasis in in vitro and in vivo models of breast cancer. Docetaxel, an anti-mitotic chemotherapeutic agent, is widely used for the treatment of castration resistant prostate cancer. However, it is associated with adverse effects and eventual drug resistance. This is the first report on the effect of combining Desmopressin and Docetaxel in prostate cancer, both in vitro and in vivo. Methods: An established castrate resistant prostate cancer cell line DU145 was used. Cellular proliferation was determined using the MTS assay. The migratory inhibition potential of Desmopressin alone and in combination with Docetaxel was accessed using the wound healing assay. In vivo evaluation was performed on a prostate cancer xenograft model using athymic nude mouse. Treatment was administered bi- weekly and tumor volume were measured throughout the treatment period. Eventually, after a six-week treatment period, tumors were excised and measured.Â Â Results: A combination therapy of 1 ÂµM Desmopressin with 100nM Docetaxel resulted in dramatic inhibition of proliferation of DU145 cells 72 hours post treatment compared to either agent along (p < 0.05). Wound healing assay revealed inhibition of cellular migration as well (p<0.05). The use of a xenograft mouse model followed by treatment with 5 mg/kg Docetaxel intraperitoneally with concomitant 2 Âµg/ml/kg Desmopressin administered intravenously 30 minutes before administering chemotherapy and 24 hours after, resulted in a significant decrease in tumor volume (P<0.05), while not impacting body weight.Conclusions: Desmopressin significantly enhanced the anti-proliferative and inhibiting the migratory potential of Docetaxel. Combination treatment had no additional effect on mice weight or mortality. These studies could enhance the efficacy of Docetaxel- based chemotherapy treatment for castrate resistant prostate cancer.

Download Full-text

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-04-2160 ◽

2005 ◽

Vol 11 (13) ◽

pp. 4851-4856 ◽

Cited By ~ 36

Author(s):

B. Liu

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Combination Therapy ◽

Cancer Cell ◽

Cell Apoptosis ◽

Prostate Cancer Cell ◽

Retinoid X Receptor ◽

Receptor Ligands

Download Full-text

Leveraging RB status to define therapy for castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.96 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 96-96

Author(s):

Renee de Leeuw ◽

Clay de Comstock ◽

Daniela de Pollutri ◽

Matthew Joseph Schiewer ◽

Stephen J Ciment ◽

...

Keyword(s):

Prostate Cancer ◽

Kinase Inhibitors ◽

Ex Vivo ◽

Tissue Samples ◽

Ki67 Staining ◽

Cell Architecture ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

96 Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.

Download Full-text

Characterisation of CCS1477: A novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11590 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11590-11590 ◽

Cited By ~ 7

Author(s):

Neil Pegg ◽

Nigel Brooks ◽

Jenny Worthington ◽

Barbara Young ◽

Amy Prosser ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Prostate Cell ◽

Molecule Inhibitor ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

And Function ◽

Prostate Cell Lines

11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.

Download Full-text

Anticancer activity of the selective CYP17A1 inhibitor, VT-464, in preclinical models of castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.104 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 104-104 ◽

Cited By ~ 1

Author(s):

Paul Toren ◽

Steven Pham ◽

Soojin Kim ◽

Hans Adomat ◽

Amina Zoubeidi ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Xenograft Model ◽

Resistant Cell ◽

Anti Cancer ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Cancer Activity

104 Background: Castrate resistant prostate cancer (CRPC) continues to be sensitive to anti-androgen therapy as evidenced by the recent successes of abiraterone acetate (AA) and enzalutamide (ENZ). VT-464 is a novel, non-steroidal, small molecule CYP17A1 inhibitor with selectivity for the lyase activity of this dual enzyme. The objective of this study was to evaluate the anti-cancer activity of VT-464 compared to AA in CRPC in vitro models that are ENZ-responsive and ENZ-resistant and in an ENZ-resistant xenograft model. Methods: In vitro studies used the human CRPC, C4-2, and ENZ-resistant cell lines, MR49C and MR49F cells, in androgen-free media. AR transcriptional activity was assessed by probasin luciferase. AR-related and steroidogenesis pathways were assessed by western blot and/or qRT-PCR. A MR49F xenograft model in castrate mice compared oral VT-464 treatment to vehicle and AA. Steroid concentrations were measured using LC-MS chromatography. Results: VT-464 demonstrated a greater decrease in AR transactivation compared to AA in C4-2 and both ENZ-resistant cell lines. A greater decrease in AR-dependent gene transcription occurred with VT-464 treatment compared to AA in all cell lines. Prostate-specific antigen (PSA) protein levels in vitro were also lower with VT-464. Gene transcripts StAR, CYP17A1, HSD17B3 and SRD5A1 increased following treatment with VT-464 both in vitro and in vivo. A greater increase was seen with VT-464 treatment compared to AA. In vivo results demonstrated greater tumor growth inhibition and decreased serum PSA levels in mice treated with oral VT-464 compared to AA. Steroid analysis revealed lower testosterone (T) and dihydrotestosterone (DHT) concentrations in C4-2 cells with VT-464 treatment compared to AA. In vivo, the intra-tumoral DHT and T levels were significantly lower in response to VT-464 or AA compared to vehicle, with the greatest decrease seen with VT-464. Conclusions: The selective CYP17 inhibitor VT-464 demonstrated anti-cancer activity in pre-clinical models of CRPC, lowering intratumoral T and DHT concentrations significantly in castrate mice. These results suggest greater androgen suppression and inhibition of AR axis signaling by VT-464 than by AA.

Download Full-text

794: Valproic Acid Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

The Journal of Urology ◽

10.1016/s0022-5347(18)33030-1 ◽

2006 ◽

Vol 175 (4S) ◽

pp. 257-257

Author(s):

Jennifer Sung ◽

Qinghua Xia ◽

Wasim Chowdhury ◽

Shabana Shabbeer ◽

Michael Carducci ◽

...

Keyword(s):

Prostate Cancer ◽

Valproic Acid ◽

Cell Growth ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Growth

Download Full-text

Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models

PLoS ONE ◽

10.1371/journal.pone.0171871 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0171871 ◽

Cited By ~ 3

Author(s):

Lucie Carolle Kenmogne ◽

Jenny Roy ◽

René Maltais ◽

Mélanie Rouleau ◽

Bertrand Neveu ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Hydroxysteroid Dehydrogenase ◽

Tumor Models ◽

Type 3

Download Full-text

A Method for Quantitative Analysis of the Kinematics of Fibroblast Migration in a Monolayer Wound Model

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53070 ◽

2011 ◽

Author(s):

Gil Topman ◽

Orna Sharabani-Yosef ◽

Amit Gefen

Keyword(s):

Wound Healing ◽

Cell Migration ◽

Wound Healing Assay ◽

Complete Coverage ◽

Time Intervals ◽

Fibroblast Migration ◽

Wound Model ◽

Regular Time

A wound healing assay is simple but effective method to study cell migration in vitro. Cell migration in vitro was found to mimic migration in vivo to some extent [1,2]. In wound healing assays, a “wound” is created by either scraping or mechanically crushing cells in a monolayer, thereby forming a denuded area. Cells migrate into the denuded area to complete coverage, and thereby “heal” the wound. Micrographs at regular time intervals are captured during such experiments for analysis of the process of migration.

Download Full-text

In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

Science Advances ◽

10.1126/sciadv.abg2564 ◽

2021 ◽

Vol 7 (27) ◽

pp. eabg2564

Author(s):

Nathalie Bock ◽

Thomas Kryza ◽

Ali Shokoohmand ◽

Joan Röhl ◽

Akhilandeshwari Ravichandran ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Advanced Prostate Cancer ◽

Adaptive Responses ◽

Metastatic Tissue ◽

Metastatic Lesions ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

Download Full-text