Table 3.
Agonists and antagonists of TLRs and their application as anticancer drugs.
| Name of the TLR(s) | Agonist/Antagonist | Associated cancer | Mechanism of action | References |
|---|---|---|---|---|
| TLR1/ TLR2 |
MALP-2 (G) | Pancreatic cancer | Inhibits tumor growth and reverses tumor-associated immunosuppression | (317) |
| Agonists: Polysaccharide-K (G) | Inhibits tumor growth and induces apoptosis in tumor cells | (318) | ||
| Bacillus Calmette–Guerin (BCG) | Bladder cancer | Used in intravesical therapy; shows antitumor activity by induction of IFN-γ and IL-2. It increases the survival of the patients | (319) | |
| Pam3CSK4 | Lymphoma | Reduces tumor load and increases the survival of the recipients | (13, 320) | |
| TLR3 | Polyriboinosinic-polyribocytidynic acid (Poly I:C) | Gastric cancer | Upregulates the pro-apoptotic genes and promotes apoptosis of the cancer cells | (35) |
| Poly(A:U) | Breast cancer | Reduces the risk of recurrence and metastasis | (102) | |
| TLR4 | Monophosphoryl lipid A (MPLA) | Colorectal cancer | Acts as a vaccine adjuvant | (321) |
| Brucella lumazine synthase (BLS) | Melanoma | Induces the secretion of INF-γ and increases the ratio of effector to regulatory cells | (36) | |
| Resatorvid (TAK-242) | Breast cell carcinoma and ovarian cancer | Regulate NF-κB signaling pathways and p53-dependent apoptotic genes, reduce the enzymatic activity of MMPs and epithelial to mesenchyme transition | (305–307) | |
| TLR7 | R-837 (Imiquimod or aldara) | Oral squamous cell carcinoma | Decreases cell growth around the transformed tissue and increases apoptotic cell death. It causes increased production of IFN-γ and less IL-10 | (6) |
| Breast cancer | Inhibits the growth of cutaneous breast cancer cells | (101) | ||
| Melanoma (Preclinical phase) | Topical application of 5% imiquimod cream on primary melanoma results in an increase in the number of CD4+ and CD8+ T cells in the skin | (322, 323) | ||
| R848 (resiquimod) | Cutaneous T-cell lymphoma (PhaseI) |
Topical administration of resiquimod affects the early stage of cutaneous T-Cell lymphoma | (322, 324) | |
| 852A | Breast-, Cervix-, and Ovarian cancers (Preclinical phase) | Enhances the expression of IP-10 and IL-13 (side effect: cardiac toxicity) |
(322, 325) | |
| Lymphomatic leukemia (Phase I/II) | Induces the expression of IgM and inflammatory cytokines | (322, 326) | ||
| Melanoma (Phase II) | Enhances the expression of IFN I and IP-10 within the serum | (322, 327) | ||
| Loxoribine (guanine ribonucleotide derivative) | B-chronic leukemia (Preclinical) | Increases the fludarabine (a purine analog) activity which leads to the induction of apoptosis. Loxoribine together with fludarabine and mafosfamide exert a synergistic effect for apoptosis induction | (322, 328, 329) | |
| TLR8 | R848 (resiquimod) | Cutaneous T-cell lymphoma (PhaseI) |
Topical application of resiquimod affects the early stage of cutaneous T-Cell lymphoma | (322, 324) |
| VTX-2337 | Lymphoma (Phase I) | Enhances the expression of G-CSF, macrophage inflammatory protein-1β, monocyte chemoattractant protein-1, and TNFα in the plasma | (330) | |
| TLR9 | CpG-ODN | T-cell lymphoma (Phase I) | PF-3512676 (formerly CPG 7909) as a TLR9 agonist exerts antitumor activity against refractory cutaneous T-cell lymphoma | (330, 331) |
| Lymphoma (phase I/II) | Triggers tumor-reactive memory CD8 T cells that lead to systemic antitumor immunity | (330, 332) | ||
| Neoplastic meningitis (Phase I) | Not determined | (330, 333) | ||
| IMO | Non-small cell lung (Phase II) | IMO-2055 acts as a TLR9 agonist in combination with bevacizumab and erlotinib and is capable to increase the anti-tumoral activity via stimulation of the immune system | (330, 334) | |
| 1018 ISS | Lymphoma (Phase II) | Enhances antigen expression, antibody-dependent cell-mediated cytotoxicity, and T helper cell type 1 shift | (330, 335) |