Table 2 Pharmacodynamic interactions between medicinal mushrooms and cytotoxic drugs in preclinical studies
Drugs | Type | Interactions with Lingzhi | Interactions with Yunzhi |
|---|---|---|---|
5-FU | Animal | Increase in tumor inhibition effect [83, 84, 98] and survival time [63] Less decrease in WBC [83, 84, 145], platelets [83] and other bone marrow cells [84] Greater recovery rate from intestinal damage caused by 5-FU [173] | Increase in survival [67], cytotoxicity and inhibit metastasis [111] Reduce immunosuppression (reduce the decrease in phagocytic activity, antibody production [111], delayed hypersensitivity [111, 112]) |
In-vitro | Increase in tumor inhibition and apoptotic rate (dose-related or time-dependent) [98,99,100,101,102,103], similar effect at lower dose of 5-FU [105] Induce cell cycle arrest at different phases [99, 101], increase caspase 3 and 8 expression and activity [100]. Increase release of cytochrome C [100, 102] and MMP [102] Increase level of DNA strand breaks and oxidative damage in cancer cells [98] | Enhance 5-FU cytotoxicity [118, 119] Decrease dihydropyrimidine dehydrogenase mRNA expression, and increase IFN-α mRNA expression [118] | |
Carboplatin | Animal | Less decrease in WBC [145] | Increase in tumor inhibition and reduce death rate [68] |
Cisplatin | Animal | Prolong survival or increase survival rate [63,64,65,66], increase [64, 66, 104, 125, 174] or no effect [146, 147, 175,176,177] on tumor inhibition, inhibit angiogenesis (decease microvessel density) [104] Influence on inflammatory cytokines (increase in interferons [146], TGF-β [127], increase or decrease in TNF-α [64, 127, 146, 159], IL [64, 127, 146, 159]) and phagocytic function [159] Increase in T cells (CD3+, CD4+, CD8+), NK cells and CD11c+ DC cells [65, 66, 125,126,127, 146] Increase blood and renocortical SOD, glutathione, GPx and reduce MDA [64, 175,176,177,178,179,180, 190,191,192] Reduces damage to liver (reduce ALT, AST) [66], kidney (reduce Scr, urea, BUN, ALP, urine NAG, toxic accumulation of plasma infiltrate, enhance CAT activity, renal structure) [64,65,66, 174,175,176,177,178,179,180, 192], intestines [173] and relieve nausea/vomiting [147, 183, 184] Modulate Bax, Bcl-2, caspase 3 [66, 125], aquaporin [125, 126], VEGF, bFGF [104, 127] expression | Increase in tumor inhibition [113] Increase in CD4+, CD4+/CD8+, decrease in CD8+ T cell [113] Upregulate Fas and caspase 3 expression, downregulate Fasl expression [113] Decrease cisplatin-induced raise in BUN and Scr [166] |
In-vitro | Increase tumor growth inhibition [104,105,106,107,108,109], apoptosis [122, 123], inhibit angiogenesis [104] Enhance drug sensitivity through the JAK–STAT3 pathway [123]. Reverse resistance [106, 109] Modulate Fas/FasL-mediated apoptosis [107] Induce cell cycle arrest by interfering with HER2/PI3K/Akt pathway [108]. Modification of the expression of TGF-β1 [105], Smad4 [105], VEGF, bFGF [104], HER2 [108], ABCB1 [122], Bax, Bad, Bcl-2, Bcl-xL [107], Akt, p53 [106] | Increase [131] or no effect [119] on tumor cell inhibition Prevent inhibition on normal cells by cisplatin [131] Prevent decrease of SOD and increase in lipid peroxide in normal cells, but opposite effect in cancer cells [131] | |
Cyclophosphamide | Animal | Increase in tumor inhibition [81, 82, 85,86,87,88,89,90,91,92,93,94] and apoptosis [81, 89, 91], suppress metastasis [90] (increase TMSG-1 expression) [91], increase in survival time [81, 82, 163] Relieve BMS, including RBC [87, 150, 156, 163, 164], WBC (NK and T cells) [81, 85, 87, 89, 90, 147,148,149,150,151,152,153,154,155,156, 158, 163], platelets [150, 153, 163], hemoglobin [163,164,165], phagocytic activity, [85, 151, 155, 156, 158, 161, 165] cytokines and antibody production [81, 88,89,90, 149, 150, 152, 153, 160] Increase antioxidant capacity, SOD, CAT, GPx and reduce MDA to normal level [81, 150] Induce loss of Bcl-2 and Bax translocation, induce release of cytochrome c, increase caspase 3 and 9 activities [81] Protect against liver (Less ALT and AST increase) [86, 164, 165] and intestine damage [173] Inhibit mutation (decrease in micronuclei frequency) [185] Reduce weight loss [85, 90, 92, 160, 163], fatigue and appetite loss [93, 94, 163, 165] | Increase in tumor inhibition [69,70,71, 112] through enhancement of cytotoxicity of lymphokine-activated killer cells and tumor-infiltrating lymphocytes [70] Reduce metastasis [70, 71] and increase survival [69,70,71] Less decrease in WBC (B and T cells, NK cells) [69, 166,167,168], hemoglobin [69] Reduce immunosuppression, increase in antibody production [112] and immunoglobulin [167] Decrease expression of immune negative transcription factors such as Foxp3, PD-1, IL-10 [171], IL-4, GATA-3 and modulate the unbalanced T helper cells [169] |
In-vitro | Increase cytotoxicity to tumor cells and drug sensitivity [103] | Enhance cytotoxicity of drug while itself has no cytotoxic effect [18] | |
Cytarabine | In-vitro | No studies available | Decrease expression of Bax, Bcl-xL and Bcl-xL/Bax ratio [128] |
Docetaxel | Animal | No studies available | Increase tumor inhibition [114, 115, 117], apoptosis [114], reduce metastasis [116] Less decrease in WBC, NK-cell [114], increase CD4+, CD8+ T cells, IL [114] Suppress induced expression of NF-kB and survivin [117] |
In-vitro | No studies available | Enhance anti-tumor effect (dose-dependent) [115, 117, 119], apoptosis [115, 120] and reduce docetaxel-enhanced invasion [115] Suppress induced expression of survivin [117], NF-kB [115, 117, 120], MMP-9 [115]. Inhibit expression of cIAP-1, enhance caspase-3 activation [120] | |
Doxorubicin | Animal | Prolong survival in additive function [63] Less decrease in WBC and platelet [157] Relieve myocardial and hepatocellular injury through modulation of enzymes (ALT, AST, LDH, CK) and oxidative stress biomarkers (GST, GPx, SOD, CAT) [157, 181, 182] | Less decrease in CD3+, CD4+ T cells, IL-2 and IL-2R expression [129, 130] |
In-vitro | Synergistic [15, 124] or no effects [14] on tumor inhibition, reverse resistance [14, 15] Increase apoptosis, decrease Ku80 and enhance reactive oxygen species production [124] | Enhance apoptotic effect [128] Increase expression of Bax, decrease Bcl-xL, Bcl-xL/Bax ratio [128] | |
Epirubicin | Animal | Less reduction of WBC [145] | No studies available |
Etoposide | Animal | No studies available | Increase tumor inhibition and reduce death rate [68] |
In-vitro | No studies available | Enhance apoptotic effect [128] Increase Bid, decrease Bcl-xL expression and Bcl-xL/Bax ratio [128] | |
Gemcitabine | In-vitro | No studies available | Additive effect in tumor growth inhibition [121] |
Mercaptopurine | Animal | No studies available | Increase delayed hypersensitivity reaction [112] |
Methotrexate | Animal | Prolong survival in additive function [66] Reduce induced small intestinal damage [162] Dose-related increase in immunoglobulin A and modulate change in oxidative stress marker such as SOD and MDA induced by methotrexate [162] | Reduce immunosuppression (increase delayed hypersensitivity reaction) [112] |
Mitomycin | Animal | No significant protection against mitomycin-induced mutation [185] | Increase in survival rate or time [72,73,74], tumor growth inhibition [73] Dose-related decrease in frequency of sister chromatid exchanges [188] Recover antibody production and delayed-type hypersensitivity [73, 112] Decrease incidence of high mobility cells, increase low mobility cells [72] |
In-vitro | Increase in cytotoxicity to tumor cells [103] Protection against mutation damage [185] | Reduce micronuclei formation in dose-related manner [187] | |
Paclitaxel | Animal | Increase in tumor inhibition [95,96,97] and efficacy of paclitaxel [95] Increase let-7 expression [95] Restore antitumorigenic immune cells via inhibiting immune checkpoints [97] Down-regulation of Warburg effect-related proteins to inhibit tumor metabolism [97] Restore gut dysbiosis induced by paclitaxel [97] | No studies available |
In-vitro | Enhance tumor growth inhibition [96, 108, 110] and apoptosis [96], reverse resistance [14] Induce cell cycle arrest by interfering with HER2/PI3K/Akt pathway [108], inhibition of HER2 signaling pathway and downregulate expression of HER2 related proteins [96, 108] | No studies available | |
Retinoic acid | Animal | Reduce neural tube defects through up-regulating the transcription of CDK4 mRNA and expression of CDK4 and nestin at neural tube epithelia [186] | No studies available |
Thioguanine | Animal | Prolong survival in additive function [63] | No studies available |
UFT/Tegafur | Animal | No significant increase in efficacy [147] Reduce damage to intestine [173] and less reduction in WBC, but not platelet [147] | Increase in cytotoxicity and inhibit metastasis [111] Reduce immunosuppression (phagocytic activity, antibody production) [111] |
Vincristine | In-vitro | Synergistic [110] or no significant effect [14] in tumor inhibition and reverse resistance [14] | No studies available |