Table 2.
Immune-modulating effects of natural compounds in tumor-bearing mice
| Compound | Doses | Animal models | Effects | Refs |
|---|---|---|---|---|
| All-trans retinoic acid (ATRA) | Subcutaneous implantation of 5 mg ATRA + PML-RARFrC DNA vaccine | Acute promyelocytic leukemia (APL) | Increased the production of IFN-γ | Furugaki, 2010 |
| Enhanced cytototoxic T cells (CD4+ and CD8+) | ||||
| All-trans retinoic acid (ATRA) | Subcutaneous implantation of 5 mg ATRA (21-day release) + HA-specific vaccine/C3 peptide-specific vaccine | 7,12-dimethylbenz(a)anthracene-induced mammalian adenocarcinoma (DA3-HA cells injected to BALB/c mice) | Decreased immature myeloid cells (ImCs) | Kusmartsev, 2003 |
| Methylcholanthrene-induced sarcoma (MethA cells injected into BALB/c mice) | ||||
| Fibrosarcoma (C3 cells injected into C57BL/6 mice) | ||||
| Curcumin | Oral 50 mg/kg on alternate days for 14 days | Ehrlich’s ascites carcinoma (EAC) cells injected into Swiss albino mice | Curumin | Bhattacharyya, 2010 |
| Diminished the Treg cell population (CD4+CD25+Foxp3+) | ||||
| Increased IFN-γ secretion, decreased production of IL-4, TGF-β, and IL-10. Reversed Th2-type immune bias | ||||
| Curcumin | Oral 50 mg/kg every day for 20–25 days | Lewis lung carcinoma (LLC) cells injected into C57BL/6 mice | Reduced the accumulation of MDSCs in spleen and tumors | Liu, 2016 |
| Promoted the maturation and differentiation of MDSCs | ||||
| Inhibited the expression of Arg-1 and ROS in purified MDSCs | ||||
| Decreased the level of IL-6 in tumor tissue and serum | ||||
| TriCurin | 1.28 mM+ TriCurin (1.28 mM curcumin + 0.32 mM epicatechin gallate + 4 mM resveratrol) | HPV+ mouse lung cancer (TC-1 cells injected into C57BL/6 mice) | Increased tumor-infiltrating NK cells and CD8+ cytolytic T cells | Mukherjee, 2018 |
| Head and neck squamous cell carcinoma (UMSCC47 cells injected into athymic nude/nude mice) | Repolarized M2-like TAMs (Arg-1highIL-10highIL-12low) to M1-like TAMs (iNOShighIL-10lowIL-12high) in the tumors | |||
| Curcumin | 0.1% in AIN-76A diet till 110 days of age | Familial adenomatous polyposis (ApcMin/+ mice) | Increased mucosal CD4+ T cells and B cells | Churchill, 2000 |
| Bisdemethoxycurcumin (BDMC) | 3 mg/kg every 3 days for 2–3 weeks, i.v. + 200 μg α-PD-L1 antibody for 2–4 weeks, i.p. | Mouse bladder carcinoma (MB49 cells injected into C57BL/6 mice) | Increased intratumoral CD8+ T cell infiltration | Shao, 2017 |
| Increased the level of IFN-γ | ||||
| Decreased the number of intratumoral myeloid-derived suppressor cells | ||||
| α-PD-L1 facilitated the secretion of IFN-γ, granzyme B, and perforin through these CD8+ T-cells | ||||
| Curcumin | Oral 0.8 or 2 g/kg curcumin daily + Listeriaat-Mage-b vaccine | Triple-negative breast cancer (4T1 cells injected into BALB/c mice) | Decreased levels of IL-6 and increased IL-12 production by MDSCs | Singh, 2013 |
| Improved CD4 and CD8 T cell responses | ||||
| TriCurin lipososme (TrLp) or curcumin liposome (CLp) | TrLp (1.28 mM+) or CLp (5 mM) daily for 5 days or every 72 h for 60 days | Mouse glioblastoma (GL261 cells injected into C57BL/6 mice) | Increased activated NK cells in tumors | Mukherjee, 2018 |
| TAMs repolarized from M2-like (Arg-1high) to M1-like (iNOShigh). | ||||
| TrLp more effective than CLp | ||||
| Curcumin–polyethylene glycol conjugate (CUR–PEG) | 40 mg/kg CUR-PET every other day, i.v. + TRP2 peptide vaccine | Melanoma (B16F10 cells injected into C57BL/6 mice) | Increased cytotoxic T lymphocyte response and IFN-γ production | Lu, 2016 |
| Decreased levels of tumor-infiltrating MDSCs and Treg cells | ||||
| Decreased levels of IL-6 | ||||
| Resveratrol | 20 mg or 50 mg/mouse on alternate days for 19 days, i.p. | Triple-negative breast cancer (4T1 cells injected into BALB/c mice) | Decreased B regulatory cells (Breg, CD25+CD81high cells within CD19+ B cells) and Foxp3+ Treg cells | Lee-Chang, 2013 |
| 50 mg or 500 mg/mouse on alternate days for 14 days, i.p. | Melanoma (B16F10 cells injected into C57BL/6 mice) | Activated CD8+ cytolytic T cells | ||
| Resveratrol | 1, 2.5, and 5 mg/kg daily for 22 days, i.p. | Renal cancer (Renca cells injected into BALB/c mice) | Increased the number and cytotoxicity of CD8+ T cells | Chen, 2015 |
| Switched from expression of Th2 cytokines (IL-6 and IL-10) to Th1 cytokines (IFN-γ) | ||||
| Resveratrol | Oral 12.5, 25, 50 mg/kg daily for 3 weeks | Mouse lymphocytic leukemia (L1210 cells injected into BALB/c mice) | Increased NK cell activity | Li, 2007 |
| Grape seed proanthocyanidins | Oral 200 mg/kg proanthocyanidins daily + 2 mg/kg doxorubicin on alternate days for 9 doses, i.p. | Mouse sarcoma (S180 cells injected into BALB/c mice) | Increased NK cell cytotoxicity and percentages of CD4+ T helper cells and CD8+ cytolytic T cells | Zhang, 2005 |
| Reversed doxorubicin-induced side effects, including lower levels of IFN-γ, IL-2 expression and NK cell function | ||||
| Polyphenon E | 0.3% in the drinking water | Mouse neuroblastomas (Transgenic TH-MYCN mice; Human SHSY5Y cells injected into NOD/SCID mice; Syngeneic Neuro 2A cells injected into A/J mice) | Shifted the balance from monocytic MDSCs (CD11b+Ly6G-Ly6high) toward granulocytic MDSCs (CD11b+Ly6G+Ly6low) | Santilli, 2013 |
| Rescued MDSC-suppressed production of IFN-γ in T cells | ||||
| Increased tumor-infiltrating CD8+ cytolytic T cells | ||||
| EGCG | 0.5 mg/mL in drinking water for 78 days + 2 μg pcDNA3-Sig/E7/LAMP-1 vaccine | E7-expressing tumors (TC-1 cells injected into C57BL/6 mice) | Increased the E7-specific CD8+ T-cell immune response (IFN-γ secretion) | Kang, 2007 |
| EGCG | Oral 5, 20, and 40 mg/kg for two weeks | Mouse leukemia (WEHI-3 cells injected into BALB/c mice) | Increased the percentages of CD3+ T cells, CD19+ B cells, and macrophages | Huang, 2013 |
| Increased NK cell activity | ||||
| Reduced the percentage of CD11b+ monocyte cells | ||||
| EGCG | Oral 2 mg | Mouse bladder cancer (MBT-2 cells injected into C3H/He mice) | Increased NK cell cytotoxicity | Hsieh, 2011 |