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. 2022 Mar 21:13:788810.
doi: 10.3389/fphar.2022.788810. eCollection 2022.

Efficacy and Pharmacological Mechanism of Poria cocos-Based Formulas Combined With Chemotherapy for Ovarian Cancer: A Integrated Systems Pharmacology Study

Affiliations

Efficacy and Pharmacological Mechanism of Poria cocos-Based Formulas Combined With Chemotherapy for Ovarian Cancer: A Integrated Systems Pharmacology Study

Xinya Peng et al. Front Pharmacol. .

Abstract

Previous studies have shown that Poria cocos-based formulas combined with chemotherapy can improve the quality of life of ovarian cancer patients. However, the results are still controversial. We systematically searched the literature from eight databases to evaluate the efficacy and safety of Poria cocos-based formulas in combination with paclitaxel-carboplatin in treating ovarian cancer (OC). Subsequently, network pharmacology, molecular docking and cell experiments were performed to further verify the underlying molecular mechanism. Thirteen randomized controlled trials, including 922 patients with OC, were enrolled in the study. The results indicated that Poria cocos-based compounds combined with paclitaxel-carboplatin significantly improved patients' tumor response rate, traditional Chinese medicine syndrome score, Karnofsky Performance Scale, physical and social function, and reduced side effects of chemotherapy compared to the paclitaxel-carboplatin alone. According to the network pharmacological analysis, tumulosic acid were the most bioactive compounds of Poria cocos. BCL2L1 is highly expressed in OC and is associated with a worse prognosis which could become potential drug target. Functional enrichment analysis suggested that the anti-OC effect of Poria cocos may be related to PI3K-Akt signaling pathway. The molecular docking results indicated that tumulosic acid might inhibit OC by regulating BCL2L1. Vitro experiment confirmed tumulosic acid that induced cell apoptosis by modulating PI3K/AKT signaling and BCL2L1. Our study may provide a clinical basis and theoretical rationale for combining Poria cocos-based formulas with chemotherapy for OC. In addition, the integrated pharmacological strategy proposed in our study provides an excellent example for exploring the mechanism of complex formulas.

Keywords: PI3K/AKT signal pathway; chemotherapy; meta-analysis; molecular docking; network pharmacology; ovarian cancer; poria cocos.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow diagram for selecting eligible studies.
FIGURE 2
FIGURE 2
Forest plot displayed the results of the meta-analysis. (A) TRR. (B) TCM syndrome score for dichotomous outcomes. (C) TCM syndrome score for continuous scales. (D) KPS for continuous scales. (E) KPS for dichotomous outcomes. KPS, Karnofsky Performance Scale.
FIGURE 3
FIGURE 3
Random effects model. (A) QOL. (B) Cognitive function. (C) Physical function. (D) Emotional function. (E) Social function.
FIGURE 4
FIGURE 4
Graded outcome data of side effects.
FIGURE 5
FIGURE 5
The process of core target screening. (A) The Venn diagram of Poria cocos and OC targets. (B) The PPI network of intersection targets. (C) The PPI network of core targets. (D) The degree value of core targets.
FIGURE 6
FIGURE 6
BCL2L1 is highly expressed in OC and correlates with poor patient prognosis. (A) Wilcoxon signed rank-sum test was used to analyze the difference in BCL2L1 expression between normal and OC samples of OC tissues in the assay GTEx. (B) Based on the CPTAC dataset, the expression levels of total BCL2L1 protein were analyzed between normal and primary tissues of OC. (C) ROC curves showed that BCL2L1 expression levels could effectively distinguish OC tissues from non-tumor tissues. The x-axis indicates the false positive rate and the y-axis indicates the true positive rate. (D) High BCL2L1 expression was correlated with poor overall survival prognosis in OC patients by GEPIA2 database analysis. (E–F) Human protein profiles showed higher BCL2L1 protein levels in OC tissues than in normal tissues (Antibody HPA035734). (G) Staining in the MCF-7 cell line revealed that BCL2L1 was localized to the mitochondria.
FIGURE 7
FIGURE 7
Network construction. (A) The H-I-T-D network. (B) The degree values of important nodes in network. (C) The H-T-P network.
FIGURE 8
FIGURE 8
Ingredient-target molecular docking. (A) The docking score of Ingredient-target. (B) The docking diagram of tumulosic acid-BCL2L1. Dashed lines represent hydrogen bonds.
FIGURE 9
FIGURE 9
(A) SKOV3 cells were treated with various concentrations tumulosic acid. Apoptosis was analyzed by flow cytometry after Annexin V-FITC/PI staining. (B) The percentage of apoptotic cells was presented as the mean ± SD of three independent experiments, ***p < 0.01. (C) Tumulosic acid or poricoic acid A inhibits the PI3K/AKT pathway in OC cells. Representative Western blots showing the status of PI3K, AKT, p-AKT, BCL2, BCL2L1 in SKOV3.
FIGURE 10
FIGURE 10
Schematic diagram of tumulosic acid acting on PI3K/AKT signaling pathway to induce apoptosis of SKOV3 cells. Combining the network pharmacology analysis and our results, we hypothesized that tumulosic acid influences the PI3K/AKT signaling pathway to regulate the expression of BCL2L1 to induce apoptosis in ovarian cancer cells.

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