scholarly journals Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models

2009 ◽  
Vol 16 (2) ◽  
pp. 401-413 ◽  
Author(s):  
Claudio Festuccia ◽  
Giovanni Luca Gravina ◽  
Anna Maria D'Alessandro ◽  
Paola Muzi ◽  
Danilo Millimaggi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Synergistic Effects ◽  
Disease Stage ◽  
Growth Delay ◽  
Complete Regression ◽  
Antitumor Effects ◽  
Aggressive Prostate Cancer ◽  
Cancer Models ◽  
Hormone Refractory

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2, and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both DTX and cisplatin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to DTX and cisplatin treatments. These combinations were also tolerable in mice and superior to either agent alone. As DTX is the standard first-line chemotherapy for HRPC, the development of DTX-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone-refractory and chemoresistant prostate tumors.

scholarly journals Humanization, Radiolabeling and Biodistribution Studies of an IgG1-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications

2021 ◽  
Vol 14 (12) ◽  
pp. 1251
Author(s):  
Joanna Strand ◽  
Kjell Sjöström ◽  
Urpo J. Lamminmaki ◽  
Oskar Vilhelmsson Timmermand ◽  
Sven-Erik Strand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Binding ◽  
Hek293 Cells ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biodistribution Studies ◽  
Indium 111 ◽  
Hormone Refractory ◽  
Theranostic Applications

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer. Targeting prostate-specific antigens whose expression is closely linked to the activity in the androgen receptor pathway, and thus the pathogenesis of prostate cancer, is a possible way to increase specificity and reduce off-target effects. We have humanized and evaluated radioimmunoconjugates of a previously murine antibody, m5A10, targeting PSA intended for theranostics of hormone-refractory prostate cancer. The humanized antibody h5A10 was expressed in mammalian HEK293 cells transfected with the nucleotide sequences for the heavy and light chains of the antibody. Cell culture medium was filtered and purified by Protein G chromatography, and the buffer was changed to PBS pH 7.4 by dialysis. Murine and humanized 5A10 were conjugated with p-SCN-Bn-CHX-A”-DTPA. Surface plasmon resonance was used to characterize the binding to PSA of the immunoconjugates. Immunoconjugates were labeled with either indium-111 or lutetium-177. Biodistribution studies of murine and humanized 5A10 were performed in mice with LNCaP xenografts. 5A10 was successfully humanized, and in vivo targeting showed specific binding in xenografts. The results thus give an excellent platform for further theranostic development of humanized 5A10 for clinical applications.

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

scholarly journals Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model

2020 ◽  
Vol 123 (7) ◽  
pp. 1089-1100 ◽  
Author(s):  
Yiannis Philippou ◽  
Hanna T. Sjoberg ◽  
Emma Murphy ◽  
Said Alyacoubi ◽  
Keaton I. Jones ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Flow Cytometry ◽  
T Cell ◽  
Dendritic Cell ◽  
Tumour Growth ◽  
Hypofractionated Radiotherapy ◽  
Growth Delay ◽  
Immune Microenvironment ◽  
Tumour Growth Delay ◽  
Cancer Models

Abstract Background Radiotherapy enhances innate and adaptive anti-tumour immunity. It is unclear whether this effect may be harnessed by combining immunotherapy with radiotherapy fractions used to treat prostate cancer. We investigated tumour immune microenvironment responses of pre-clinical prostate cancer models to radiotherapy. Having defined this landscape, we tested whether radiotherapy-induced tumour growth delay could be enhanced with anti-PD-L1. Methods Hypofractionated radiotherapy was delivered to TRAMP-C1 and MyC-CaP flank allografts. Tumour growth delay, tumour immune microenvironment flow-cytometry, and immune gene expression were analysed. TRAMP-C1 allografts were then treated with 3 × 5 Gy ± anti-PD-L1. Results 3 × 5 Gy caused tumour growth delay in TRAMP-C1 and MyC-CaP. Tumour immune microenvironment changes in TRAMP-C1 at 7 days post-radiotherapy included increased tumour-associated macrophages and dendritic cells and upregulation of PD-1/PD-L1, CD8+ T-cell, dendritic cell, and regulatory T-cell genes. At tumour regrowth post-3 × 5 Gy the tumour immune microenvironment flow-cytometry was similar to control tumours, however CD8+, natural killer and dendritic cell gene transcripts were reduced. PD-L1 inhibition plus 3 × 5 Gy in TRAMP-C1 did not enhance tumour growth delay versus monotherapy. Conclusion 3 × 5 Gy hypofractionated radiotherapy can result in tumour growth delay and immune cell changes in allograft prostate cancer models. Adjuncts beyond immunomodulation may be necessary to improve the radiotherapy-induced anti-tumour response.

Clinical, Cellular, and Molecular Evidence of the Additive Antitumor Effects of Biguanides and Statins in Prostate Cancer

2020 ◽  
Author(s):  
Juan M Jiménez-Vacas ◽  
Vicente Herrero-Aguayo ◽  
Antonio J Montero-Hidalgo ◽  
Prudencio Sáez-Martínez ◽  
Enrique Gómez-Gómez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Agents ◽  
Signalling Pathways ◽  
Molecular Evidence ◽  
Male Population ◽  
Antitumor Effects ◽  
Clinical Safety ◽  
Inhibition Of Proliferation ◽  
Prostate Cell

Abstract Context Prostate cancer (PCa) is one of the leading causes of cancer-related death among the male population worldwide. Unfortunately, current medical treatments fail to prevent PCa progression in a high percentage of cases; therefore, new therapeutic tools to tackle PCa are urgently needed. Biguanides and statins have emerged as antitumor agents for several endocrine-related cancers. Objective To evaluate: (1) the putative in vivo association between metformin and/or statins treatment and key tumor and clinical parameters and (2) the direct effects of different biguanides (metformin/buformin/phenformin), statins (atorvastatin/simvastatin/lovastatin), and their combination, on key functional endpoints and associated signalling mechanisms. Methods An exploratory/observational retrospective cohort of patients with PCa (n = 75) was analyzed. Moreover, normal and tumor prostate cells (normal [RWPE-cells/primary prostate cell cultures]; tumor [LNCaP/22RV1/PC3/DU145 cell lines]) were used to measure proliferation/migration/tumorsphere-formation/signalling pathways. Results The combination of metformin+statins in vivo was associated to lower Gleason score and longer biochemical recurrence-free survival. Moreover, biguanides and statins exerted strong antitumor actions (ie, inhibition of proliferation/migration/tumorsphere formation) on PCa cells, and that their combination further decreased; in addition, these functional parameters compared with the individual treatments. These actions were mediated through modulation of key oncogenic and metabolic signalling pathways (ie, AR/mTOR/AMPK/AKT/ERK) and molecular mediators (MKI67/cMYC/androgen receptor/cell-cycle inhibitors). Conclusions Biguanides and statins significantly reduced tumor aggressiveness in PCa, with this effect being more potent (in vitro and in vivo) when both compounds are combined. Therefore, given the demonstrated clinical safety of biguanides and statins, our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa.

scholarly journals Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3631
Author(s):  
Ketaki Gadkari ◽  
Urvi Kolhatkar ◽  
Rutu Hemani ◽  
Gisella Campanelli ◽  
Qing Cai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Inhibitory Effects ◽  
Antitumor Effects ◽  
Anticancer Effects ◽  
Potent Inhibition ◽  
Avian Erythroblastosis Virus

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

Metronomic chemotherapy for hormone refractory prostate cancer (HRPC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15649-15649
Author(s):  
S. Hoshi ◽  
K. Numahata ◽  
K. Hoshi ◽  
K. Suzuki ◽  
K. Ono ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
Bone Scan ◽  
Performance Status ◽  
Metronomic Chemotherapy ◽  
Response Duration ◽  
Complete Regression ◽  
Hormone Refractory Prostate Cancer ◽  
Median Response ◽  
Hormone Refractory

15649 Background: Low dose continuous chemotherapy (metronomic chemotherapy) is trying to many advanced cancers. Metronomic chemotherapy has important anti-angiogenic activity to tumor vessels. For patients who progressed after docetaxel, no standard options exist. We have experienced complete regression of bone metastases on super scan by low does cisplatin, UFT, diethylstilbestrol, and dexamethasone (CUDD) in a patient with HRPC (Int JCO, 8,118, 2003). Methods: CUDD consisting of weekly 5 mg/body of cisplatin plus 125 mg/body of diethylstilbestrol and daily 300–450 mg of UFT/day plus 0.5–1 mg of dexamethasone were given to 47 HRPC patients, (median and range of age: 66 and 52–72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 10 patients and 8 in 17 patients and 9 in 20 patients, respectively. Metastatic site was bone in 45 (EOD grade 1:10, 2:18, 3: 15, 4:2), lymph node in 8. Six cases became refractory to docetaxel were treated with CUDD plus CPM (50 mg/day). Results: Among the 45 patients assessable for bone metastasis, 12 (27 %) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 9 were EOD grade 1–3. Eighteen (40 %) were stable and 15 (33%) progressed on bone scan. Among 8 patients of lymph node metastasis, 3 (38%) showed partial response, 2 (25%) no change and 3 (38%) progression. Twenty-five (53 %) out of 47 patients showed a PSA decline of 50% or greater. Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. Their median response duration and median survival time were 8 months (range; 2 to 44 months) and 20 months (range, 4 to 48 months), respectively. Their median response duration was 3 months. Three of 6 refractory to docetaxel were responded to CUDD plus CPM. Their median response duration was 10 months. Conclusions: CUDD is effective in almost half of hormone refractory prostate cancer patients and has advantage of minimal side effect. Three of 6 docetaxel refractory cases also responded to CUDD plus CPM. No significant financial relationships to disclose.

scholarly journals Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2387
Author(s):  
Amandine Rambur ◽  
Marine Vialat ◽  
Claude Beaudoin ◽  
Corinne Lours-Calet ◽  
Jean-Marc Lobaccaro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Improve Patient Care ◽  
Accessory Gland ◽  
In Vivo Model ◽  
Cancer Models ◽  
Aging Men ◽  
Functional Equivalent ◽  
High Level

Prostate cancer is the most common cancer in aging men. Despite recent progress, there are still few effective treatments to cure its aggressive and metastatic stages. A better understanding of the molecular mechanisms driving disease initiation and progression appears essential to support the development of more efficient therapies and improve patient care. To do so, multiple research models, such as cell culture and mouse models, have been developed over the years and have improved our comprehension of the biology of the disease. Recently, a new model has been added with the use of the Drosophila accessory gland. With a high level of conservation of major signaling pathways implicated in human disease, this functional equivalent of the prostate represents a powerful, inexpensive, and rapid in vivo model to study epithelial carcinogenesis. The purpose of this review is to quickly overview the existing prostate cancer models, including their strengths and limitations. In particular, we discuss how the Drosophila accessory gland can be integrated as a convenient complementary model by bringing new understanding in the mechanisms driving prostate epithelial tumorigenesis, from initiation to metastatic formation.

Sign in / Sign up

Export Citation Format

Share Document