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) [98–103], 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 [63–66], increase [64, 66, 104, 125, 174] or no effect [146, 147, 175–177] 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, 125–127, 146] Increase blood and renocortical SOD, glutathione, GPx and reduce MDA [64, 175–180, 190–192] 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) [64–66, 174–180, 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 [104–109], 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, 85–94] 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, 147–156, 158, 163], platelets [150, 153, 163], hemoglobin [163–165], phagocytic activity, [85, 151, 155, 156, 158, 161, 165] cytokines and antibody production [81, 88–90, 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 [69–71, 112] through enhancement of cytotoxicity of lymphokine-activated killer cells and tumor-infiltrating lymphocytes [70] Reduce metastasis [70, 71] and increase survival [69–71] Less decrease in WBC (B and T cells, NK cells) [69, 166–168], 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] Increase Bax, decrease Bcl-2 and CDK4 [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 [72–74], 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 [95–97] 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