Table 1.
Examples studied agents for the inhibition of IL-6 signalling with an emphasis on their clinical applicability.
| Name (Trade Name) | Target: Function | Status | Ref. |
|---|---|---|---|
| Human monoclonal antibody | |||
| Tocilizumab (RoActemra) | IL-6R: receptor inhibition | Clinically used for rheumatoid arthritis | [47] |
| Case report: Reducing IL-6-mediated cachexia | [48] | ||
| Sarilumab (Kevzara) | IL-6R: receptor inhibition | Clinically used for rheumatoid arthritis | [49] |
| Under clinical trial (EMPOWER NCT04333706): triple-negative breast cancer (stage I-III, high-risk residual diseases) combination with Capecitabine | |||
| Siltuximab | IL-6: neutralization | approved for CAR-T | [50] |
| Low molecular inhibitor | |||
| Bazedoxifene (Conbriza) | Estrogen receptor modulator | Clinically used in the treatment of osteoporosis | [51] |
| gp130: inhibitor | In vivo | [52] | |
| CD40 receptor: inhibitor | In vitro | [53] | |
| Tofacitinib (Xeljanz) | JAK1/3 inhibitor | Clinically used in the treatment of moderate-severe ulcerative colitis | [54] |
| JAK pathway | Clinical trial: developed malignancies lung, breast, gastric cancer, and lymphoma; rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time | [55] | |
| Ruxolitinib (Jakafi) | JAK1/2 inhibitor | Clinically used in the treatment of steroid refractory graft-versus-host disease | [56] |
| JAK pathway | Clinical trials: inadequately controlled polycythaemia; decrease in thromboembolic events | [57] | |
| Momelotinib | ACVR1/ALK2, JAK1 and JAK2, inhibitor | FDA accepts for the treatment of the myelofibrosis | |
| Momelotinib | Clinical trials: myelofibrosis; higher overall and leukaemia-free survival. | [58] | |
| Madindoline A and B | gp130: inhibitor | In vitro | [59,60] |
| ERBF | IL-6R: blocking interaction IL-6R with IL-6, or gp130 | In vivo | [61,62,63] |
| Stattic | STAT3: inhibition of activation | In vivo | [64] |
| OPB-31121 | STAT3: inhibition of activation | Clinical trials: advanced colon and rectal tumours; tumour shrinkage, bad pharmacokinetic (very low blood concentration) | [65,66] |
| Galiellalactone | STAT3: inhibition of DNA binding | prostatectomy samples: reduction IL-6 induced AR signalling | [67] |
| In vivo | [68] | ||
| GPB730 | STAT3: inhibition of DNA binding | In vivo | [69] |
| OPB-51602 | STAT3: activation of aggregation | Clinical trials: refractory haematological malignancies; no clear therapeutic response was observed | [70] |
| Ixazomib | NF-κB: inhibition of ubiquitin-proteasome pathway leading to loss of NF-κB activity | Clinical trials: Relapsed or Refractory Cutaneous or Peripheral T-cell Lymphomas; reduction in NF-κB activation and subsequently GATA-3 expression in the biopsy specimens | [71] |
| Theofyline (Elixophyllin, Elixophylline, Pulmophylline, Quibron-T, Theo-24, Theolair, Uniphyl) | phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator | Clinically used in chronic obstructive pulmonary disease and asthma | [72,73] |
| NF-κB: inhibition of activation | In vitro | [74] | |
| Rapamycin (Sirolimus, Rapamur) | mTOR: inhibitor | Clinically used immunosuppressive therapy | [75] |
| Clinical trials: acute myelogenous leukaemia; no effects on the composite complete remission rate | [76] | ||
| IL-6, TNF-α and IL-1β: decrease cytokine level | In vivo | [77] | |
| Zotarolimus | IL-1β, TNF-α, IL-6 and NF-κB: decrease cytokine level and NF-KB activity | In vivo | [78] |
|
NSAIDs (e.g., celecoxib, aspirin, ibuprofen, naproxen, meloxicam) |
cyclooxygenase inhibitors | in a broad spectrum of conditions; Analgetic, antipyretics, in rheumatic diseases | [79] |
| Celecoxib | IL-6: decrease expression by COX-2 inhibition | Clinical trials: former-smokers; bronchoscopy samples (reduction IL-6 and Ki-67 expression) | [80] |
| Food supplements | |||
| Curcumin | IL-6: decrease expression | Clinical trials: patients with solid tumour; decrease in plasma level of IL-6, TNF-a, TGF-b, substance P, hs-CRP, CGRP and MCP-1, increase patient quality life | [81] |
| STAT3: decrease activity | In vivo | [82] | |
| NF-κB: activity and expression | Clinical trials: advanced pancreatic cancer; peripheral blood mononuclear cells (decrease in expression of NF-κB, STAT-3 and COX-2) decrease in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists) | [83] | |
| HIF-1α: decrease expression and activity | In vitro and In vivo | [84,85] | |
| Epigallocatechin-3-gallate | NF-κB: decrease expression | Clinical trial: subjects with a high risk of colorectal cancer; lover expression of the NF-κB and DNMT1 | [86] |
| STAT3: inhibition of activation | Molecular assay and In vitro | [87] | |