Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Role and Regulation of IL-8 and CXCR1/2 in Prostate Cancer
2.1. IL-8: Role and Regulation
2.2. CXCR1 and CXCR2: Expression and Signalling Pathways
3. Impact of IL-8/CXCR1/2 on the Tumour Microenvironment
3.1. Vascular Dynamics and Cancer Cell Communication
Cancer Stem Cell-Mediated Tumour Progression and Treatment Resistance
3.2. Immunosuppressive TME
3.3. Modulation of Immune Response and Inflammation
3.4. Cancer Cell Plasticity: Induction of Epithelial–Mesenchymal Transition (EMT) and Metastasis
4. TME and Its Significance in Cancer
4.1. ECM
4.2. Heterogeneity
4.3. Inflammation
4.4. Immune Response
5. Therapeutic Implications and Challenges
5.1. Therapeutic Implications
5.2. Therapeutic Inhibition of CXCL8/CXCR1/CXCR2: Small-Molecule Inhibitors, Antagonists, and Monoclonal Antibodies
5.3. Combinational Therapies and Emerging Treatment Modalities
5.4. Clinical Trials
6. Challenges in Implementing Therapies Targeting IL-8-CXCR1/2 Axis for PCa Treatment
6.1. Development of Treatment Resistance
6.2. Specificity and Efficacy of CXCR1/2 Targeting
6.3. Side Effects
7. Discussion and Conclusions
8. Future Directions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ACE | Proof of Concept Phase I/II Trial of the CXCR2 Antagonist AZD5069, Administered in Combination with enzalutamide, in Patients with Metastatic Castration-Resistant Prostate Cancer |
ADT | Androgen deprivation therapy |
AKT | Protein kinase B |
AR | Androgen receptor |
ASIs | Androgen-signalling inhibitors |
BSP | Bone sialoprotein |
CAFs | Cancer-associated fibroblasts |
CD3+ T-cells, CD20+ B-cells, NK cells | Immune cells including T-cells, B-cells, and natural killer cells |
CRPC | Castration-resistant prostate cancer |
CSCs | Cancer stem cells |
CTLA-4 | Cytotoxic T-Lymphocyte Antigen 4 |
CTLA-5 | Cytotoxic T-Lymphocyte Antigen 5 |
CXCL8 | Chemokine (C-X-C motif) Ligand 8 (IL-8) |
CXCR1 | C-X-C chemokine receptor type 1 |
CXCR2 | C-X-C chemokine receptor type 2 |
ECM | Extracellular matrix |
ECs | Endothelial cells |
EGF | Epidermal growth factor |
EMT | Epithelial–mesenchymal transition |
ENA-78 | Epithelial-derived neutrophil-activating peptide 78 |
FDA | U.S. Food and Drug Administration |
FGF | Fibroblast growth factor |
GEMMs | Genetically engineered mouse model |
Gleason score | A grading system for the histological patterns of prostate cancer |
GPCR | G protein-coupled receptor |
HCC | Hepatocellular carcinoma |
hCXCR1 K1 | Human CXCR1 knock-in |
IGF | Insulin-like growth factor |
IL-6 | Interleukin-6 |
IL-8 | Interleukin-8 |
IR | Ionizing radiation |
JAK2 | Janus kinase |
KDM5C | Lysine (K)-specific Demethylase 5C |
MAPK | Mitogen-activated protein kinase |
mCRPC | Metastatic castration-resistant prostate cancer |
MDSCs | Myeloid-derived suppressor cells |
MMPs | Matrix metalloproteinases |
MSCs | Mesenchymal stem cells |
mTOR | Mammalian Target of Rapamycin |
NEPC | Neuroendocrine prostate cancer |
NF-kB | Nuclear Factor Kappa B |
NK Cells | Natural killer cells |
NLR | Neutrophil-to-lymphocyte ratio |
P53 | Tumour protein p53 |
PARP | Polyadenosine-diphosphate-ribose polymerase |
PCa | Prostate cancer |
PD-1 | Programmed cell death protein 1 |
PDGF | Platelet-derived growth factor |
PD-L1 | Programmed death-ligand 1 |
PDXs | Patient-derived xenografts |
PI3K/AKT | Phosphoinositide 3-kinase/protein kinase B |
PKC | Protein kinase C |
PMN | Polymorphonuclear |
PSA | Prostate-specific antigen |
PSMA | Prostate-specific membrane antigen |
PTEN | Phosphatase and Tensin Homolog |
RNA | Ribonucleic acid |
RNT | Radionuclide therapy |
STAT3 | Single Transducer and Activation of Transcription |
TAMs | Tumour-associated macrophages |
TGF-β | Transforming growth factor-beta |
TILs | Tumour-infiltrating lymphocytes |
TME | Tumour microenvironment |
TMPRSS-ERG | Transmembrane Protease, Serine 2—Erythroblast Transformation-Specific (ETS)-Related Gene |
TNF | Tumour necrosis factor |
TNFRSF14 | Tumour necrosis factor Receptor Superfamily Member 14 |
TNF-α | Tumour necrosis factor-alpha |
UBE2R2-AS1 | Ubiquitin-Conjugating Enzyme E2 R2 Antisense RNA 1 |
VEGF | Vascular Endothelial Growth Factor |
VEGF-A | Vascular Endothelial Growth Factor A |
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Species | IL-8 Ligands | CXCR1/CXCR2 Ligands | CXCR1 Expression | CXCR2 Expression |
---|---|---|---|---|
Human | IL-8 (CXCL8) | CXCR1: CXCL6, CXCL8 CXCR2: CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8 | Yes | Yes |
Mouse | KC (CXCL1), MIP-2 (CXCL2), Gro-alpha (CXCL1) | CXCR1: CXCL6 CXCR2: CXCL1, CXCL2, CXCL3, CXCL5, CXCL6 | No | Yes |
Inhibitor | Clinical Development | CXCR1 | CXCR2 | IL-8 | |
---|---|---|---|---|---|
Navarixin (SCH-527123) | Phase 2 | COPD Asthma Psoriasis Solid tumours | |||
Reparixin | Phase 3 Pneumonia | Pneumonia Acute respiratory distress syndrome Diabetes mellitus Solid tumours | |||
SB225002 | |||||
SB265610 | |||||
SX-682 | Phase 1 and 2 | Myelodysplastic syndromes Solid tumours | |||
AZD5069 | Phase I2 Asthma Phase 1 and 2 mCRPC | Asthma Brochiectasis Solid tumours Pancreatic cancer HCC HNSCC | |||
Danirixin (GSK1325756) | Phase 1/2 | COPD Viral disease | |||
Benzoylaconitine | |||||
Pectolinarin | |||||
Auraotene | |||||
CXCR2 antagonist 4 | |||||
DF2726A | |||||
BMS-986253 (HuMax-IL8) | Phase 1/2 | MDS Solid tumours |
Drug Name | Trial Name | Target | Type | Last Reported Status | Summary | NCT Number | Results |
---|---|---|---|---|---|---|---|
AZD5069 (Astrazeneca) | ACE | CXCR2 | Small-molecule inhibitor | Phase 1 and 2: completed | AZD5069 in combination with enzalutamide. | NCT03177187 | Results described in Section 4.3 |
Navarixin (Merck) | CXCR1/2 | Small-molecule inhibitor | Phase 1 and 2: completed | Navarixin (MK-7123) in combination with pembrolizumab (MK-3475) in adults with selected advanced/metastatic solid tumours. | NCT03473925 | Results posted on clinical trials.gov | |
BMS-986253 (Previously Humax IL-8) (Bristol-Myers Squibb) | MAGIC-8 | IL-8 | mAb | Phase 1b/2: active, not recruiting | Nivolumab (anti-PD-1) or nivolumab plus BMS-986253 in combination with ADT using degarelix (LHRH antagonist) for men with hormone-sensitive prostate cancer and a rising prostate-specific antigen (PSA). | NCT03689699 | No results posted |
Burixafor Hydrobromide | CXCR4 | Pilot study: completed | Investigate single-agent burixafor hydrobromide, docetaxel, and G-CSF. Burixafor hydrobromide, alone or in combination with G-CSF, is currently in Phase 2 testing for use as a hematopoietic stem cell (HSC) mobilization agent. | NCT02478125 | No results posted |
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McClelland, S.; Maxwell, P.J.; Branco, C.; Barry, S.T.; Eberlein, C.; LaBonte, M.J. Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance. Cancers 2024, 16, 2797. https://doi.org/10.3390/cancers16162797
McClelland S, Maxwell PJ, Branco C, Barry ST, Eberlein C, LaBonte MJ. Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance. Cancers. 2024; 16(16):2797. https://doi.org/10.3390/cancers16162797
Chicago/Turabian StyleMcClelland, Shauna, Pamela J. Maxwell, Cristina Branco, Simon T. Barry, Cath Eberlein, and Melissa J. LaBonte. 2024. "Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance" Cancers 16, no. 16: 2797. https://doi.org/10.3390/cancers16162797
APA StyleMcClelland, S., Maxwell, P. J., Branco, C., Barry, S. T., Eberlein, C., & LaBonte, M. J. (2024). Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance. Cancers, 16(16), 2797. https://doi.org/10.3390/cancers16162797