Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments
Abstract
:1. Introduction
1.1. Background on Bone Metastases
1.2. Pathophysiology of Bone Metastases
1.3. Introduction to Interleukins
1.4. Interleukins in the Immune Modulation
1.5. Influence of Interleukins on the Bone Microenvironment
1.6. Impact on the Immune Microenvironment in Bone Metastases
2. Interleukins and Cancer
2.1. Pro-Inflammatory Interleukins and Cancer
2.2. Pro-Inflammatory Interleukins and Bone Metastases
2.3. Anti-Inflammatory Interleukins and Cancer
2.4. Anti-Inflammatory Interleukins and Bone Metastases
3. Signaling Pathways Involved
3.1. NF-κB Pathway
3.2. JAK/STAT Pathway
3.3. MAPK Pathway
4. Therapeutic Implications of Targeting Interleukins
4.1. Current Therapeutic Approaches for Bone Metastases
4.2. Overview of Drugs Targeting Interleukins
4.2.1. Tocilizumab
4.2.2. Siltuximab (CNTO 328)
4.2.3. Bimekizumab
4.2.4. ANV419
4.2.5. Canakinumab
4.2.6. Denosumab
4.3. Summary of Clinical Trials and Outcomes
4.4. Combinational Therapies
4.5. Treatment Challenges and Limitations
4.6. Cost Effectiveness
5. Interleukins as Diagnostic and Prognostic Biomarkers
6. Gaps in Current Research and Future Directions
6.1. Research Gaps
6.2. Future Directions
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Therapeutic Agent | Target Interleukin | Mechanism of Action | Clinical Application | Challenges/Limitations |
---|---|---|---|---|
Tocilizumab | IL-6 | Inhibits IL-6 receptor | Rheumatoid arthritis, potential in reducing bone metastases | Infections, liver enzyme elevation |
Siltuximab | IL-6 | Neutralizes IL-6 bioactivity | Prostate cancer, ovarian cancer | Resistance, cytokine release syndrome |
Bimekizumab | IL-17A and IL-17F | Dual inhibition of IL-17A and IL-17F | Psoriatic arthritis, potential in bone healing | Long-term safety, high cost |
ANV419 | IL-2Rβγ | Selective IL-2Rβγ binding agonist | Advanced solid tumors | Grade 1/2 adverse events |
Canakinumab | IL-1β | IL-1β inhibition | Rheumatoid arthritis, potential in bone metastases | Expensive, risk of infections |
Denosumab | RANKL | Inhibits RANK/RANKL interaction | Bone metastases from solid tumors | Osteonecrosis of the jaw, hypocalcemia |
Drug | Dose | Clinical Effect | Side Effects | Clinical Study | Animal Study |
---|---|---|---|---|---|
Tocilizumab | 8 mg/kg IV every 4 weeks | Reduces inflammation, improves symptoms in RA and other conditions | Infections, elevated liver enzymes | Effective in reducing bone metastases in preclinical studies; used in RA and Castleman’s disease; investigated in other conditions (Crohn’s disease, SLE) | Reduced bone metastases in animal models of breast cancer; inhibited cell survival and reduced expressions of Stat3, VEGF, and RANK in MDA-231 cells |
Siltuximab | 11 mg/kg IV every 3 weeks | Neutralizes IL-6, reduces tumor cell survival, enhances chemotherapy effects | Infections, neutropenia, thrombocytopenia | Inhibits proliferation of prostate cancer cells in vitro; extends disease stability; reduces levels of TNF-α, IL-1, CCL2, CXCL12, and VEGF | Inhibits androgen-dependent prostate cancer progression in mice; reduces cachexia levels in prostate cancer models |
Bimekizumab | 160–320 mg SC every 4 weeks | Dual neutralization of IL-17A and IL-17F, improves bone health | Infections, nasopharyngitis, oral candidiasis | Effective in hidradenitis suppurativa and spondyloarthritis; improves key outcomes such as disease activity, functional status, and quality of life | Inhibits osteogenic differentiation and bone formation in human periosteum-derived cell models; improves bone healing and regeneration in osteoporotic models |
ANV419 | 243 µg/kg IV every 2 weeks | Enhances tumor-killing capabilities of immune cells, minimizes immunosuppressive cell activation | Chills, low-grade fever | Phase I/II study showed well-tolerated, disease stabilization in solid tumors; phase I study demonstrated antitumor activity with stable disease and partial response in advanced tumors | Stimulates immune cells selectively, enhancing tumor-killing capabilities while minimizing activation of immunosuppressive cells |
Canakinumab | 150–300 mg SC every 4 weeks | Reduces inflammation, slows bone metastasis progression | Infections, neutropenia, thrombocytopenia | Ongoing trials for various solid tumor malignancies; reduces metastasis and bone tumor growth in preclinical studies | Inhibits breast cancer growth and bone metastasis in preclinical models; reduces metastasis and metastatic outgrowth in bone with VX765 and Anakinra |
Denosumab | 120 mg SC every 4 weeks | Inhibits bone resorption, delays skeletal-related events, improves quality of life | Hypocalcemia, osteonecrosis of the jaw | Effective in delaying skeletal-related events in breast and prostate cancer; superior to bisphosphonates in delaying skeletal-related events | Increases serum IL-8 levels, promoting osteoclast formation even without RANKL activity; combination with IL inhibitors may enhance treatment outcomes |
Interleukin | Type | Role | Diagnostic Biomarker | Prognostic Biomarker |
---|---|---|---|---|
IL-1 | Pro-inflammatory | Promotes osteoclastogenesis, tumor proliferation, angiogenesis | Elevated IL-1 levels in patient serum indicate active inflammation and metastasis | High IL-1 levels correlate with increased tumor burden and poor prognosis |
IL-6 | Pro-inflammatory | Promotes osteoclastogenesis, tumor proliferation, angiogenesis | Elevated IL-6 levels indicate tumor activity and systemic inflammation | High IL-6 levels correlate with advanced disease and poor prognosis |
IL-8 | Pro-inflammatory | Stimulates osteoclastogenesis, promotes angiogenesis | Elevated IL-8 levels indicate active metastatic process | High IL-8 levels correlate with increased metastatic potential and poor prognosis |
IL-11 | Pro-inflammatory | Promotes osteoclastogenesis and bone degradation | Elevated IL-11 levels are associated with active bone resorption | High IL-11 levels correlate with bone metastasis and worse clinical outcomes |
IL-17 | Pro-inflammatory | Enhances osteoclastogenesis, promotes tumor cell survival | Elevated IL-17 levels indicate aggressive disease | High IL-17 levels correlate with poor survival and increased bone destruction |
IL-18 | Pro-inflammatory | Modulates tumor microenvironment and tumor development | Elevated IL-18 levels are associated with tumor progression | High IL-18 levels correlate with poor patient outcomes |
IL-4 | Anti-inflammatory | Inhibits osteoclast activity, modulates immune responses | Elevated IL-4 levels indicate anti-inflammatory response | High IL-4 levels correlate with better clinical outcomes and reduced bone resorption |
IL-10 | Anti-inflammatory | Inhibits osteoclast activity, promotes immune regulation | Elevated IL-10 levels indicate anti-inflammatory state | High IL-10 levels correlate with reduced tumor progression and better prognosis |
IL-13 | Anti-inflammatory | Inhibits osteoclast activity, modulates immune responses | Elevated IL-13 levels indicate anti-inflammatory environment | High IL-13 levels correlate with better prognosis and reduced metastatic potential |
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Dawalibi, A.; Alosaimi, A.A.; Mohammad, K.S. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments. Int. J. Mol. Sci. 2024, 25, 8163. https://doi.org/10.3390/ijms25158163
Dawalibi A, Alosaimi AA, Mohammad KS. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments. International Journal of Molecular Sciences. 2024; 25(15):8163. https://doi.org/10.3390/ijms25158163
Chicago/Turabian StyleDawalibi, Ahmad, Amal Ahmed Alosaimi, and Khalid S. Mohammad. 2024. "Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments" International Journal of Molecular Sciences 25, no. 15: 8163. https://doi.org/10.3390/ijms25158163