Experimental Treatment Efficacy of dmrFABP5 on Prostate Cancer Singly or in Combination with Drugs in Use DOI Open Access

Saud A Abdulsamad,

Abdulghani A Naeem,

Hao Zeng

et al.

Published: July 13, 2023

Enzalutamide is a drug used to treat PC. Docetaxel for chemotherapy different cancers including prostate cancer (PC). The effectiveness of these drugs in treating castration-resistant (CRPC) not consistent and thus, CRPC still an incurable disease. Recent evidence showed that the bio-inhibitor FABP5, dmrFABP5, suppressed tumorigenicity metastasis cells. In this work, we studied possible synergic effect dmrFABP5 combined with either or on suppressing PC A highly significant was observed when combination androgen-responsive cells 22RV1. also 22RV1 malignant, androgen-receptor (AR)-negative DU145 These applications exhibited inhibitory action viability, migration, invasion colony formation abilities both 22RV1and However, did produce any suppression FABP5-negative cell line LNCaP, although can significantly suppress LNCaP as single agent. Further investigations suggested synergistic effects were produced by interrupting FABP5-related signal transduction pathway

Language: Английский

Development of a Double-Stapled Peptide Stabilizing Both α-Helix and β-Sheet Structures for Degrading Transcription Factor AR-V7 DOI Creative Commons
Bohan Ma,

Donghua Liu,

Mengjun Zheng

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(2), P. 816 - 827

Published: Jan. 29, 2024

Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, permeability. Nonetheless, while has successfully stabilized α-helical peptides, it shown applicability for most β-sheet motifs. In this study, we present design of a novel double-stapled capable simultaneously stabilizing both α-helix structures. Our designed peptide, named DSARTC, specifically targets androgen receptor (AR) DNA binding domain MDM2 E3 ligase. Serving peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits ability degrade full-length AR AR-V7. Molecular dynamics simulations circular dichroism analysis validate successful constraint secondary structures, demonstrating that "first-in-class" heterogeneous-conformational drug candidate. Compared its linear counterpart, displays enhanced an improved cell ability. enzalutamide-resistant prostate cancer animal model, effectively inhibits tumor growth reduces levels AR-V7 proteins. These results highlight potential more potent specific Furthermore, our findings provide promising expanding staple drugs, targeting wide range "undruggable" transcription factors.

Language: Английский

Citations

13
Androgen receptor dynamics in prostate cancer: from disease progression to treatment resistance DOI Creative Commons
Caihong Li,

Dongkai Cheng,

Peng Li

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 11, 2025

Prostate cancer is the most common among men worldwide, especially in those over 65, and a leading cause of cancer-related mortality. The disease typically advances from an androgen-dependent state to castration-resistant prostate (CRPC), which poses significant treatment challenges. androgen receptor (AR) on X chromosome central driver this process, activating genes that govern proliferation survival. Mutations amplifications AR are closely associated with progression resistance. While traditional therapies such as deprivation therapy (ADT) antagonists like enzalutamide have been effective, resistance persists due reactivation signaling through mechanisms ligand-independent activation. Recent research highlights role epigenetic modifications enhancing activity drug tumor microenvironment, particularly interactions cancer-associated fibroblasts (CAFs) tumor-associated macrophages (TAMs), further complicates by promoting aggressive behavior immune evasion. Future directions include developing next-generation antagonists, identifying AR-related biomarkers for personalized therapy, exploring combinations checkpoint inhibitors. Additionally, basal cell-lumen-derived organoids provide innovative models can enhance understanding strategies cancer.

Language: Английский

Citations

1
Insulin‐Like Growth Factor 2 mRNA‐Binding Protein 2 (IGF2BP2) Promotes Castration‐Resistant Prostate Cancer Progression by Regulating AR‐V7 mRNA Stability DOI Creative Commons

Taruna Saini,

Devesh Srivastava, Rajnikant Raut

et al.

Cancer Reports, Journal Year: 2025, Volume and Issue: 8(2)

Published: Feb. 1, 2025

ABSTRACT Background The emergence of constitutively active androgen receptor (AR) splice variant AR‐V7 poses a formidable challenge in treating prostate cancer, as it lacks the ligand binding region targeted by androgen‐deprivation therapies such enzalutamide and abiraterone. is critical for castration‐resistant cancer (CRPC) development progression; however, molecular mechanisms regulating its expression biological function remain poorly understood. Here, we investigate role IGF2BP2 CRPC progression. Methods To determine clinical relevance CRPC, analyzed mRNA data patients available Genomic Data Commons (GDC) Portal cBioPortal. Next to resistance, performed shRNA‐mediated knockdown overexpression experiments followed qRT‐PCR, immunoblot, colony‐formation, MTT assays. Finally, RIP‐qPCR, actinomycin‐D, domain‐deletion analysis study mechanism which regulates stability, expression, resistance cells. Results Our revealed that upregulated positively correlates with increasing Gleason score CRPC. We demonstrate silencing leads downregulation downstream target genes without affecting AR levels. Additionally, also enhances sensitivity cells while increases confers increased enzalutamide. Mechanistically, our binds intronic splicing enhancer (ISE) AR‐V7, thereby enhancing stability. Furthermore, pinpoints KH3 KH4 domains stability resistance. Conclusions Taken together, findings suggest plays offering novel developing therapeutic interventions

Language: Английский

Citations

1
Novel hormone therapies for advanced prostate cancer: understanding and countering drug resistance DOI Creative Commons
Zhipeng Wang, Jie Wang,

Dengxiong Li

et al.

Journal of Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown, P. 101232 - 101232

Published: Feb. 1, 2025

Language: Английский

Citations

1
CRISPR genome-wide screening identifies PAK1 as a critical driver of ARSI cross-resistance in prostate cancer progression DOI
Haojie Chen, Keqin Dong, Jie Ding

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216725 - 216725

Published: Feb. 15, 2024

Language: Английский

Citations

8
MED12 and CDK8/19 modulate androgen receptor activity and enzalutamide response in prostate cancer DOI Creative Commons

Chiara Andolfi,

Caterina Bartolini,

Elisa Morales

et al.

Endocrinology, Journal Year: 2024, Volume and Issue: 165(10)

Published: Aug. 27, 2024

Abstract Prostate cancer progression is driven by androgen receptor (AR) activity, which a target for therapeutic approaches. Enzalutamide an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One these expression AR-V7, constitutively active splice variant. The Mediator complex multisubunit protein modulates gene on genome-wide scale. MED12 cyclin-dependent kinase (CDK)8, or paralog CDK19, are components module regulates proliferation cells. In this study, we investigated how CDK8/19 influence cancer-driven processes in cell lines, focusing activity enzalutamide response. We inhibited LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), PC3 (AR−, enzalutamide-insensitive) Both inhibition reduced all respective 3D spheroids. knockdown significantly c-Myc signaling pathways. cells, it consistently response, prostate-specific antigen (PSA) secretion, genes, AR-V7 expression. Combined enzalutamide, additively decreased both PSA secretion cells and, when combined Our study revealed regulate their may modulate response to

Language: Английский

Citations

8
Hydrophobic tagging of small molecules: an overview of the literature and future outlook DOI
Yang Zhou, Fan Zhou, Shujing Xu

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(7), P. 799 - 813

Published: June 2, 2024

Introduction Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims provide overview of the HyT literature and future outlook offer guidance for

Language: Английский

Citations

6
Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models DOI Creative Commons
Pengfei Xu, Joy C. Yang, Shu Ning

et al.

Pharmacological Research, Journal Year: 2023, Volume and Issue: 189, P. 106692 - 106692

Published: Feb. 10, 2023

Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology U-box-containing 1 (HSP70/STUB1) machinery are involved androgen receptor (AR) AR variant stabilization. Targeting HSP70 could be a viable strategy to overcome resistance signaling inhibitor (ARSI) advanced cancer. Here, we showed that novel allosteric inhibitor, JG98, significantly drug-resistant C4-2B MDVR CWR22Rv1 cell growth, enhanced treatment. JG98 also growth conditional reprogramed cultures (CRCs) organoids derived from patient samples. Mechanistically, degraded AR/AR-V7 expression cells promoted STUB1 nuclear translocation bind AR-V7. Knockdown of E3 ligase diminished anticancer effects partially restored AR-V7 inhibitory JG98. JG231, more potent analog developed effectively CRCs, organoids. Notably, combination JG231 synergistically inhibited xenograft tumor growth. Inhibition using small-molecule inhibitors coordinates with regulate stabilization ARSI resistance.

Language: Английский

Citations

11
Selective Adsorption of Human Testosterone from Plasma Using Zn2+-Loaded Hexanediamine–Chitosan Beads DOI Creative Commons

Huibin Yu,

Hongqin Ke,

Chen Tu

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

This study aimed to develop a novel adsorbent, Zn2+ -loaded hexanediamine-chitosan (HDA-CS) beads, for the selective removal of human testosterone from plasma. The preparation involved synthesizing chitosan modifying them with hexanediamine enhance adsorption capacity and subsequently loading zinc ions. effects HDA spacer, concentration, time on percentage were systematically investigated through series experiments. Results indicated that -HDA-CS beads achieved maximum approximately 35% within 90 min. analysis plasma concentrations , albumin, sex hormone-binding globulin (SHBG) process complex interaction between testosterone-bound SHBG albumin binding sites beads. Additionally, adsorbent demonstrated good storage stability selectivity testosterone, minimal impact total protein content in These findings highlight potential as an effective therapeutic option managing levels clinical settings, particularly patients undergoing androgen deprivation therapy prostate cancer.

Language: Английский

Citations

0
Integrated bioinformatics analysis reveals that OPRK1 inhibits ferroptosis and induces enzalutamide resistance in prostate cancer DOI Creative Commons

Liangrong Zhang,

Yanqin Liu, Xiaodong Wen

et al.

European journal of medical research, Journal Year: 2025, Volume and Issue: 30(1)

Published: April 15, 2025

Language: Английский

Citations

0