<i>Cordyceps sinensis mycelium</i> Refined Polysaccharides Regulate PI3K/AKT/mTOR Pathway to Inhibit Hepatocellular Carcinoma and its Synergistic Effect on Cyclophosphamide

Background Cordyceps sinensis is a unique and precious Traditional Chinese Medicine. The fermented mycelia of C. sinensis are obtained from the medicinal strains isolated from C. sinensis by liquid-submerged fermentation, which have similar pharmacological effects to natural C. sinensis . Polysaccharide is one of the main components of natural and artificial Cordyceps , which has anti-tumor effects and is currently used in the adjuvant treatment of various cancers. However, the anti-hepatoma efficacy of C. sinensis fermented mycelia polysaccharides and the underlying mechanism have not been reported, and the synergistic effect of combined treatment with cyclophosphamide (CTX) remains to be explored. Objectives Investigating the effects of the refined polysaccharide Cordyceps polysaccharide 1 (CP1) from C. sinensis mycelium on the PI3K/AKT/mTOR pathway in HepG2 hepatocellular carcinoma cells, and its detoxifying effect when combined with CTX. Materials and Methods The subcutaneous transplantation tumor model of human hepatocellular carcinoma HepG2 in nude mice was established. The tumor volume and weight were recorded, and the tumor inhibition rates were calculated. Enzyme-linked immunosorbent assay (ELISA) was used to examine the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and vascular endothelial growth factor (VEGF) secretions in cancerous tissues. Immunohistochemical methods were used to identify the expression rates of BAX and BCL-2 genes associated with apoptosis in cancerous tissues. Western blotting was used to identify the levels of protein expression in the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Mice had their peripheral blood collected for standard blood testing. Results Tumor suppression percentages for the CP1 high-, medium-, and low-dosage categories stood at 46.60%, 45.18%, and 36.84%, respectively. CP1 increased the secretion of TNF-α and decreased the secretion of VEGF, IL-6, and IL-1β in tumor tissues. There was a decrease in the expression of the anti-apoptotic protein B-cell lymphoma-2 (BCL-2) and an increase in the expression of the pro-apoptotic protein BCL2-associated X (BAX). There was a decrease in the phosphorylation levels of PI3K, AKT, and mTOR proteins within tumor tissues. Tumor suppression percentages for CTX, CP1 high, medium, and low doses in conjunction with CTX groups stood at 71.29%, 77.63%, 76.98%, and 75.24%, respectively. In groups receiving high, medium, and low doses of CP1 along with CTX, there was an elevation in the spleen coefficient and the count of leukocytes, neutrophils, and lymphocytes in peripheral blood. Conclusion CP1 can significantly and effectively inhibit the growth of hepatocellular carcinoma, and its mechanism may be related to the inhibition of protein expression of the PI3K/AKT/mTOR signaling pathway. The combination of CP1 and CTX can increase the anti-tumor effect and alleviate the bone marrow suppression of CTX.