Synergistic Antitumor Effect of Grifola frondose Polysaccharide—Protein Complex in Combination with Cyclophosphamide in H22 Tumor-Bearing Mice

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy and remains a global health threat. The objective of the current study was to determine whether the combination of a cold-water extracted polysaccharide-protein complex from Grifolia frondosa (GFG) and cyclophosphamide (CTX) could inhibit tumor growth by suppressing the expression of angiogenesis-related proteins in H22 tumor-bearing mice. The results showed that the inhibition rate of GFG combined with CTX on H22 tumors was 65.29%, which was significantly higher than that of GFG treatment alone (24.82%). GFG combined with CTX significantly increased the expression levels of vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9. Additionally, thymus index, spleen index, natural killer (NK) cell activity, interferon-γ (IFN-γ), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) levels increased significantly after GFG treatment, especially after high-doses of GFG combined with CTX treatment (p < 0.05). The thymus index, spleen index, NK cell activity, IFN-γ, IL-1β, TNF-α, and IL-2 levels were 1.90, 1.46, 1.30, 2.13, 1.64, 2.03, and 1.24 times of those treated with CTX alone. Thus, we proposed that GFG can alleviate the side effects of CTX by relieving the immunosuppressive effect, liver/renal injury, and oxidative stress. In conclusion, the combination of GFG and CTX for cancer treatment may be a promising strategy, and GFG is expected to be a potential adjuvant alternative for the treatment of HCC.