scholarly journals Cytotopic (Cyto-) IL-15 as a New Immunotherapy for Prostate Cancer: Recombinant Production in Escherichia coli and Purification

2021 ◽  
Vol 8 ◽  
Author(s):  
Ana M. Esteves ◽  
Efthymia Papaevangelou ◽  
Dorota Smolarek ◽  
Prokar Dasgupta ◽  
Christine Galustian
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Inclusion Bodies ◽  
Great Efficacy ◽  
Prostate Tumors ◽  
Protein Variant ◽  
Recombinant Production ◽  
C Terminus ◽  
Reduce Tumor Growth ◽  
The One

Interleukin-15 (IL-15) is a cytokine previously suggested as a potential immunotherapy for cancer treatment. IL-15 can effectively reduce tumor growth in many preclinical tumor models including prostate cancer. This is due to its ability to expand and activate immune cells, such as CD8+ T cells and natural killer cells. To increase the potency of IL-15, we have engineered a protein variant that can be modified to localize and be retained in tissues where it is administered. However, the production of recombinant IL-15, the purity, and correct refolding of the final protein is not always ideal. In the current study, we aimed to optimize the methodology for production and purification of a modified recombinant human IL-15 and investigate the efficacy of the produced protein in the treatment of prostate tumors. Human IL-15 with its polypeptide sequence modified at the C-terminus to enable thiol conjugation with membrane localizing peptides, was produced in E. coli and purified using mild denaturing conditions (2M urea) from a washing step or from solubilization of inclusion bodies. The purified protein from the wash fraction was conjugated to a myristoylated peptide to form a membrane-localizing IL-15 (cyto-IL-15). The efficacy of cyto-IL-15 was investigated in subcutaneous TRAMP-C2 prostate tumors in mice and compared with cyto-IL-15 derived from protein purified from inclusion bodies (cyto-IL-15 Gen). When mild denaturing conditions were used for purification, the largest amount of IL-15 was collected from the wash fraction and a smaller amount from inclusion bodies. The protein from the wash fraction was mainly present as a monomer, whereas the one from inclusion bodies formed homodimers and higher complexes. After cytotopic modification, the purified IL-showed great efficacy in delaying prostate tumor growth (∼50%) and increased mice survival by ∼1.8-fold compared with vehicle. This study demonstrates an alternative, inexpensive and efficient method to produce and purify a modified version of IL-15 using mild denaturing conditions. This IL-15, when cytotopically modified, showed great efficacy as a monotherapy in prostate tumors in mice further highlighting the potential of IL-15 as a cancer immunotherapy.

The effect of VERU-111, a novel oral inhibitor of α and β tubulin, on tumor growth in the human castration-resistant, AR-variant prostate cancer (PCa) model 22Rv1.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 167-167
Author(s):  
Mark Christopher Markowski ◽  
Robert H. Getzenberg ◽  
Mitchell S. Steiner ◽  
Nilofer Saba Azad ◽  
Mario A. Eisenberger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Splice Variants ◽  
Phase 1 ◽  
Blocking Agent ◽  
Multi Drug Resistance ◽  
Tubulin Inhibitor ◽  
Castration Resistant ◽  
Reduce Tumor Growth ◽  
Β Tubulin

167 Background: VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance. In xenograft mouse models of taxane responsive and resistant cancers, VERU-111 results in tumor inhibition at ≤20 mg/kg orally dosed infrequently as 1/week. VERU-111 and docetaxel were tested in the human PCa model, 22Rv1, which expresses androgen receptor splice variants, including AR-V7, and is resistant to abiraterone and enzalutamide. Methods: Human 22Rv1 cells were implanted into SCID mice. When tumors reached 150-200 mm , the animals were randomized into 4 groups (n = 10 per group): PO vehicle; PO VERU-111 5 or 20 mg/kg; or IP docetaxel 10 mg/kg 3X per week. Animal weights and tumor volumes were measured 2X week and at study end. Animals were removed from study when the tumor volume exceeded 2000 mm or upon treatment for 28 days. Results: VERU-111 (PO 5 and 20 mg/kg) 3X/week significantly reduced tumors by 31% (p = 0.049) and 49% (p = 0.010), respectively, compared to vehicle. Administration of 10 mg/kg docetaxel IP had a nonsignificant reduction in tumor size. With respect to toxicity, mice treated with oral VERU-111 either significantly gained (5 mg/kg) or maintained their weight (20 mg/kg), whereas the docetaxel treated mice lost weight (p = 0.013). There was a significantly greater weight in mice treated with VERU-111 versus docetaxel (p = 0.014). Conclusions: VERU-111, a next generation, orally α and β tubulin inhibitor, has significant anti-tumor activity against PCa and other tumors. In the human PCa model 22Rv1, VERU-111 had a statistically significant reduction in tumor growth and was well tolerated. In contrast, IP docetaxel did not significantly reduce tumor growth and had greater toxicity. A phase 1/2 trial evaluating VERU-111 in men with metastatic castration and novel androgen blocking agent (abiraterone or enzalutamide) resistant prostate cancer is in progress. [Table: see text]

scholarly journals A rise in T3/T4 ratio reduces the growth of prostate tumors in a murine model

2020 ◽  
Vol 247 (3) ◽  
pp. 225-238
Author(s):  
Ana Sánchez-Tusie ◽  
Carlos Montes de Oca ◽  
Julia Rodríguez-Castelán ◽  
Evangelina Delgado-González ◽  
Zamira Ortiz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Body Weight ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Cancer Cell Line ◽  
The Body ◽  
Prostate Tumors ◽  
Mouse Prostate

Thyroxine (T4) promotes cell proliferation and tumor growth in prostate cancer models, but it is unknown if the increase in the triiodothyronine (T3)/T4 ratio could attenuate prostate tumor development. We assessed T3 effects on thyroid response, histology, proliferation, and apoptosis in the prostate of wild-type (WT) and TRAMP (transgenic adenocarcinoma of the mouse prostate) mice. Physiological doses of T3 were administered in the drinking water (2.5, 5 and 15 µg/100 g body weight) for 6 weeks. None of the doses modified the body weight or serum levels of testosterone, but all of them reduced serum T4 levels by 50%, and the highest dose increased the T3/T4 ratio in TRAMP. In WT, the highest dose of T3 decreased cyclin D1 levels (immunohistochemistry) but did not modify prostate weight or alter the epithelial morphology. In TRAMP, this dose reduced tumor growth by antiproliferative mechanisms independent of apoptosis, but it did not modify the intraluminal or fibromuscular invasion of tumors. In vitro, in the LNCaP prostate cancer cell line, we found that both T3 and T4 increased the number of viable cells (Trypan blue assay), and only T4 response was fully blocked in the presence of an integrin-binding inhibitor peptide (RGD, arginine-glycine-aspartate). In summary, our data show that the prostate was highly sensitive to physiological T3 doses and suggest that in vivo, an increase in the T3/T4 ratio could be associated with the reduced weight of prostate tumors. Longitudinal studies are required to understand the role of thyroid hormones in prostate cancer progression.

815: Human Kallikrein 2 (HK2) Inhibitors Suppress Tumor Growth of Prostate Cancer Xenografts in Nude Mice

2006 ◽  
Vol 175 (4S) ◽  
pp. 263-263
Author(s):  
Christoph Kündig ◽  
Sylvain M. Cloutier ◽  
Steve Aellen ◽  
Loyse M. Felber ◽  
Jair R. Chagas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Nude Mice ◽  
Human Kallikrein 2 ◽  
Kallikrein 2

scholarly journals Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

2021 ◽  
Vol 14 (2) ◽  
pp. 103
Author(s):  
Zohaib Rana ◽  
Joel D. A. Tyndall ◽  
Muhammad Hanif ◽  
Christian G. Hartinger ◽  
Rhonda J. Rosengren
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Hdac Inhibitors ◽  
G1 Arrest ◽  
Prostate Cancer Cells ◽  
Prostate Tumors ◽  
Normal Prostate ◽  
Pc3 Cells ◽  
Du145 Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

scholarly journals CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2872
Author(s):  
Aaron R. Waddell ◽  
Haojie Huang ◽  
Daiqing Liao
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Cell Cycle Progression ◽  
Hormone Receptors ◽  
Steroid Hormone Receptors ◽  
Breast Cancers ◽  
Creb Binding Protein ◽  
Breast And Prostate Cancer

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

Prostate Cancer: Population-Based Survival Rates in Central Italy

1995 ◽  
Vol 81 (2) ◽  
pp. 81-85 ◽  
Author(s):  
Emanuele Crocetti ◽  
Eva Buiatti ◽  
Andrea Amorosi
Keyword(s):  
Prostate Cancer ◽  
Central Italy ◽  
Survival Rates ◽  
Relative Survival ◽  
Tumor Grade ◽  
Population Based ◽  
Prognostic Effect ◽  
Disease Extension ◽  
The One ◽  
Histological Verification

Aims To evaluate survival in prostate cancer patients in the Province of Florence where the Tuscany Cancer Registry is active. Methods The survival of 777 patients with prostate cancer diagnosed in the period 1985-87 was evaluated. The observed and relative survival rates 1, 3 and 5 years after diagnosis were computed. Also the prognostic effect of age, disease extension, tumor grade, histological verification, place of residence and year of diagnosis were evaluated using univariate and multivariate analysis. Results The observed survival was 73.4% 1 year, 42.5% 3 years and 29.2% 5 years after diagnosis. The relative survival was respectively 78.7%, 53.0% and 43.0%. Significant independent risks were evident when the disease was extended out of the prostate, for patients older than 80 years, for high grade tumors and for patients without histological verification. Conclusion The 5-year relative survival rate in the province of Florence is similar to those from other European Registries and the Latina Registry, but much lower than the one reported by the SEER program in the US. Data on histological verification percentage, availability of information on disease extension, and tumor grade are discussed as indicators of the quality of the diagnostic approach in comparison with other registries.

EFFECT OF INTERMITTENT FASTING ON PROSTATE CANCER TUMOR GROWTH IN A MOUSE MODEL

2009 ◽  
Vol 181 (4S) ◽  
pp. 53-53
Author(s):  
Jean A Thomas ◽  
Susan Poulton ◽  
Tameika Phillips ◽  
Jessica C. Lloyd ◽  
Jodi Antonelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Intermittent Fasting ◽  
Cancer Tumor

Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer

2015 ◽  
Vol 64 (7) ◽  
pp. 873-883 ◽  
Author(s):  
Vladimir Riabov ◽  
David Kim ◽  
Surmeet Chhina ◽  
Richard B. Alexander ◽  
Elena N. Klyushnenkova
Keyword(s):  
Prostate Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Tumor Associated Macrophages ◽  
Hla Dr

scholarly journals Downregulation and Prognostic Performance of MicroRNA 224 Expression in Prostate Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 261-269 ◽  
Author(s):  
Konstantinos Mavridis ◽  
Konstantinos Stravodimos ◽  
Andreas Scorilas
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Prognostic Indicator ◽  
Disease Stage ◽  
Clinical Value ◽  
Prostate Tumors ◽  
Tissue Samples ◽  
Total Rna

INTRODUCTION The extensive use of prostate-specific antigen as a general prostate cancer biomarker has introduced the hazards of overdiagnosis and overtreatment. Recent studies have revealed the immense biomarker capacity of microRNAs (miRNAs) in prostate cancer. The aim of this study was to analyze the expression pattern of miR-224, a cancer-related miRNA, in prostate tumors and investigate its clinical utility. METHODS Total RNA was isolated from 139 prostate tissue samples. After the polyadenylation of total RNA by poly(A) polymerase, cDNA was synthesized with a suitable poly(T) adapter. miR-224 expression was assessed by quantitative real-time PCR and analyzed with the comparative quantification cycle method, Cq(2−ΔΔCq). We performed comprehensive biostatistical analyses to explore the clinical value of miR-224 in prostate cancer. RESULTS miR-224 expression was significantly downregulated in malignant samples compared with benign samples (P < 0.001). Higher miR-224 expression levels were found in prostate tumors that were less aggressive (P = 0.017) and in an earlier disease stage (P = 0.018). Patients with prostate cancer who were positive for miR-224 had significantly enhanced progression-free survival intervals compared with miR-224–negative patients (P = 0.021). Univariate bootstrap Cox regression confirmed that miR-224 was associated with favorable prognosis (hazard ratio 0.314, P = 0.013); nonetheless, multivariate analysis, adjusted for conventional markers, did not identify miR-224 as an independent prognostic indicator. CONCLUSIONS miR-224 is aberrantly expressed in prostate cancer. Its assessment by cost-effective quantitative molecular methodologies could provide a useful biomarker for prostate cancer.

Sign in / Sign up

Export Citation Format

Share Document