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. 2021 Apr 20;41(4):504-513.
doi: 10.12122/j.issn.1673-4254.2021.04.04.

[Synergistic effect of polysaccharide from Trichoderma pseudokoningii and oxaliplatin on colorectal cancer cells in vitro]

[Article in Chinese]
P Li  1   2 , P Yuan  1   2 , Y Que  1 , X Liu  3 , G Wang  1   2
Affiliations

[Synergistic effect of polysaccharide from Trichoderma pseudokoningii and oxaliplatin on colorectal cancer cells in vitro]

[Article in Chinese]
P Li et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To explore the synergistic inhibitory effect of polysaccharide from Trichoderma pseudokoningii (EPS) and oxaliplatin (Oxa) on colorectal cancer (CRC) HCT116 cells.

Objective: HCT116 cells were treated with 8 μg/mL Oxa and 100 μg/mL EPS alone or in combination, and the changes in cell viability was assessed with CCK-8 assay. CompuSyn software was used for fitting the Fa-CI curve to evaluate the combined effect of the two agents. Flow cytometry was performed to analyze cell apoptosis and cell cycle changes, and wound healing assay and Transwell assay were used to examine the migration ability of the treated cells. Oxa- and EPS-related genes and CRC-related genes were intersected for protein-protein interaction (PPI) analysis and GO and KEGG enrichment analyses.

Objective: Treatment with Oxa alone or in combination with EPS significantly inhibited the viability of HCT116 cells in a dose- and time-dependent manner, and the two agents exhibited a significant synergistic effect (CI < 1). The combined treatment with Oxa and EPS resulted in a significantly higher total cell apoptosis rate and a higher percentage of cells in S phase than Oxa alone and the control treatment (P < 0.05). EPS and Oxa alone both inhibited the migration of HCT116 cells, and their combination produced a stronger inhibitory effect. GO enrichment analysis of the key genes related with Oxa, EPS and CRC suggested that these genes were involved mainly in such biological processes as exogenous apoptosis signaling, cell response to chemical stress, and reactive oxygen metabolism; KEGG analysis showed that these genes were involved in the pathways of drug resistance, apoptosis and angiogenesis.

Objective: EPS and Oxa can synergistically inhibit the proliferation of HCT116 cells possibly through the PI3K-Akt, MAPK, VEGF, and p53 signaling pathways.

目的: 探讨拟康氏木霉胞外多糖（EPS）联合奥沙利铂（Oxa）用药对结肠癌细胞HCT116的协同抑制作用。

方法: 实验分为Control组（0 μg/mL）、Oxa组（8 μg/mL Oxa）、EPS组（100 μg/mL EPS）、EPS+Oxa组（8 μg/mL Oxa+100 μg/mL EPS）。CCK-8检测细胞活力，CompuSyn软件拟合Fa-CI曲线评价联用效果。流式检测凋亡和周期、划痕实验和transwell实验检测细胞迁移能力，Oxa和EPS相关基因与结直肠癌相关基因取交集进行PPI分析以及GO和KEGG富集分析。

结果: Oxa单用或与EPS联用处理HCT116细胞，均可使HCT116细胞活力受到抑制，并呈现剂量与时间依耐性，两者联用有明显的协同作用（CI < 1）。两药联用组的细胞总凋亡率与Oxa组以及对照组比较均显著升高（P < 0.05）；联合用药组处于S期的比例高于其他各组。EPS和Oxa均具有抑制HCT116细胞迁移的作用，两者联用后抑制作用更为明显。KEGG分析显示主要涉及耐药、凋亡、血管新生等通路。

结论: EPS联合奥沙利铂可协同抑制HCT116细胞增殖，促进该细胞凋亡和细胞S周期阻滞、抑制细胞迁移，铂耐药、PI3K-Akt、MAPK等信号通路发挥了关键作用。

Keywords: Trichoderma pseudokoningii; colorectal cancer; oxaliplatin; polysaccharide; synergy.

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Figures

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奥沙利铂与EPS对HCT116细胞增殖活力的影响 Effects of oxaliplatin and polysaccharide from Trichoderma pseudokoningii (EPS) on proliferation of HCT116 cells.
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EPS与奥沙利铂联用对结肠癌细胞增殖的协同抑制作用 EPS and oxaliplatin (Oxa) synergistically inhibit HCT116 cell proliferation. A: Inhibition rates of HCT116 cells incubated with Oxa and with Oxa + EPS (1∶12.5) for 24, 48, and 72 h determined by CCK-8 assay. Data are presented as Mean ± SD of 3 independent experiments. B: Combination index (CI) for EPS and oxaliplatin in HCT116 cells.
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流式细胞术检测各给药组对人结肠癌细胞HCT116细胞凋亡的影响 Flow cytometric analysis of apoptosis rates of HCT116 cells treated with 100 μg/mL EPS, 8 μg/mL oxaliplatin, or both (Mean±SD, n=3). *P < 0.05 vs control group; #P < 0. 05 vs Oxa group.
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流式细胞术检测各给药组作用于人结肠癌细胞HCT116后诱导细胞周期的作用 Flow cytometry for analyzing cell cycle changes in HCT116 cells treated with 100 μg/mL EPS, 8 μg/mL oxaliplatin, or both.
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拟康氏木霉胞外多糖联用奥沙利铂对HCT116细胞的影响 Effect of EPS (100 μg/mL) combined with oxaliplatin (8 μg/mL) on migration ability of HCT116 cells. A: Wound healing assay (Original magnification: × 100). B: Transwell migration assay (×100).
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核心靶点的筛选 Screening of the core targets. A: Oxaliplatin 2D structure. B: Drug-disease intersection genes. C: PPI network and key protein modules. D: Target connection top 30 genes.
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GO富集分析（排名前10） GO Enrichment analysis of the top 10 genes.
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KEGG富集分析（排名前30） KEGG enrichment analysis of the top 30 genes.
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PI3K-Akt信号通路图（hsa04151） PI3K-Akt signaling pathway (hsa04151).
See this image and copyright information in PMC

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