scholarly journals The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2929
Author(s):  
Yi-Hua Sheng ◽  
Wohn-Jenn Leu ◽  
Ching-Nung Chen ◽  
Jui-Ling Hsu ◽  
Ying-Tung Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Mitochondrial Dysfunction ◽  
Anticancer Activity ◽  
Intracellular Signaling ◽  
G1 Phase ◽  
G1 Arrest ◽  
Ros Production ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.

scholarly journals Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ding-fang Zhang ◽  
Zhi-chun Yang ◽  
Jian-qiang Chen ◽  
Xiang-xiang Jin ◽  
Yin-da Qiu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Adhesion ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Dna Damage And Repair ◽  
Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

scholarly journals HES6 drives a critical AR transcriptional programme to induce castration‐resistant prostate cancer through activation of an E 2 F 1‐mediated cell cycle network

2014 ◽  
Vol 6 (5) ◽  
pp. 651-661 ◽  
Author(s):  
Antonio Ramos‐Montoya ◽  
Alastair D Lamb ◽  
Roslin Russell ◽  
Thomas Carroll ◽  
Sarah Jurmeister ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 205-205
Author(s):  
Joseph R. Bertino ◽  
Zoltan Szekely ◽  
Kathleen W Scotto
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Replication Proteins ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Stability

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.

scholarly journals Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells

2019 ◽  
Author(s):  
Julie Pratibha Singh ◽  
Manisha Dagar ◽  
Gunjan Dagar ◽  
Sudhir Rawal ◽  
Ravi Datta Sharma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Prostate Tumor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Pka Pathway ◽  
Adhesion Gpcr

AbstractThe androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating a role for these in CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all prostate tumor samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.

TACC2 Is an Androgen-Responsive Cell Cycle Regulator Promoting Androgen-Mediated and Castration-Resistant Growth of Prostate Cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Tumor Formation ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Castration Resistant ◽  
Hormone Refractory ◽  
Immunocompromised Mice

Despite the existence of effective antiandrogen therapy for prostate cancer, the disease oftenprogresses to castration-resistant states. Elucidation of the molecular mechanisms underlying theresistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathwaysis a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy,we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. Wediscovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coilprotein 2 (TACC2), is a novel androgen-regulated gene.Weidentified a functional AR-binding site(ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, inwhich activated hallmarks of histone modification were observed. Androgen-dependent TACC2induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitorbicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstratedthat TACC2 is highly expressed and contributes to hormone-refractory proliferation, assmall interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression.By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. Invivo tumor formation study of prostate cancer in castrated immunocompromised mice revealedthat TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstratedby a correlation between high TACC2 expression and poor survival rates. Taken togetherwith the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer thatthe molecule is a potential therapeutic target in CRPC

Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 197-197
Author(s):  
Jingsong Zhang ◽  
David D. Chism ◽  
Scott T. Tagawa ◽  
Paul Monk ◽  
Robert S. Alter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Anticancer Activity ◽  
Nuclear Export ◽  
Second Generation ◽  
Phase 1 ◽  
Single Agent ◽  
Resistant Cell ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Tumor Activity

197 Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.

scholarly journals Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer

2017 ◽  
pp. 1-11 ◽  
Author(s):  
G. Celine Han ◽  
Justin Hwang ◽  
Stephanie A.M. Wankowicz ◽  
Zhenwei Zhang ◽  
David Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Deprivation Therapy ◽  
Second Generation ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Line Of Therapy

Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A ( CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade—palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

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