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. 2024 Oct 23:15:1449498.
doi: 10.3389/fphar.2024.1449498. eCollection 2024.

Effect of fermentation on the constituents in the branches and leaves of Taxus media and non-small cell lung cancer

Xing Guo  1 , Rui-Sheng Wang  1 , Zhen-Ling Zhang  1   2   3   4 , Hong-Wei Zhang  1 , Sheng-Chao Wang  1 , Shuai Zhang  1 , Ya-Ning Wu  1 , Ya-Jing Li  1 , Jun Yuan  1
Affiliations

Effect of fermentation on the constituents in the branches and leaves of Taxus media and non-small cell lung cancer

Xing Guo et al. Front Pharmacol. .

Abstract

Introduction: Non-small cell lung cancer (NSCLC) is a prominent lung cancer disease worldwide. Currently, commonly used methods, such as surgery and radiotherapy, have significant side effects. Traditional Chinese medicine (TCM) has become a research hotspot because of its safe and effective characteristics. The branches and leaves of Taxus media are abundant in antitumor active compounds, and there has been no research conducted as yet regarding its anti-lung cancer molecular mechanism.

Objective: The aim of this study is to investigate the antitumor activity of two samples before and after fermentation of T. media, and to research the molecular mechanism of its inhibitory effect on NSCLC.

Methods: The chemical composition of pre-fermentation T. media (TM) and post-fermentation T. media qu (TMQ) were investigated using UHPLC-Q-Qrbitrap HRMS and high-performance liquid chromatography (HPLC). The anti-lung cancer activities of TM and TMQ were compared using an A549-induced tumor mouse model. An enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence were used to determine the of TMQ mechanism of action.

Results: The results indicated that TM and TMQ contained 83 compounds, consisting primarily of flavonoids, organic acids, and taxanes. Both taxanes and flavonoids in TMQ were higher than that in TM. Both TM and TMQ effectively inhibited the tumor growth in non-small cell lung cancer (NSCLC), and the inhibition rate was greater in TMQ (57.24%) than in TM (49.62%). TMQ administration downregulated the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the glutathione (GSH) level and upregulated interferon-γ (IFN-γ), reactive oxygen species (ROS), and malondialdehyde (MDA) levels in the serum of tumor mice. TMQ treatment also increased the protein expression of Bax, Caspase-3, and Beclin-1 in tumor tissues. In contrast, the bcl-2, PI3K, Ki67, ULK1, and mTOR protein levels were suppressed by TMQ. Protein assay analyses reemphasized the superior antitumor effect of TMQ over TM. These cumulative findings demonstrated that the mechanism of action of TMQ was closely related to the activation of transcriptional misregulation in the cancer pathway that inhibited the cholinergic synaptic, AMPK, and PI3K/Akt/mTOR signaling pathways.

Conclusion: This study demonstrated that fermentation increased the active ingredient contents and antitumor effects of T. media. In addition, post-fermentation TMQ was superior to TM as a herbal medicine for NSCLC treatment.

Keywords: Taxus media2; antitumor activity4; fermentation3; herbal medicine5; non-small cell lung cancer1.

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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
Schematic diagram of the technical process.
FIGURE 2
FIGURE 2
Total ion chromatograms (TICs) of TM and TMQ. (TM+) TIC of TM in positive ion mode; (TM-) TIC of TM in negative ion mode; (TMQ+) TIC of TMQ in positive ion mode; (TMQ-) TIC of TMQ in negative ion mode.
FIGURE 3
FIGURE 3
The effects of TM and TMQ on A549 cells viability were determined by CCK8 assay. The A549 cells were treated with 0–64 mg/mL of TM and 0–64 mg/mL of TMQ for 12, and 48 h. Data are presented as mean ± S.D. values of three experiments. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to the control (0 mg/mL).
FIGURE 4
FIGURE 4
The effects of TM and TMQ on tumor tissue.
FIGURE 5
FIGURE 5
Effects of TM and TMQ on the histopathology of mouse tumor tissues (200×) (n = 3).
FIGURE 6
FIGURE 6
Results of immune factors and oxidative stress indexes. (A) IFN-γ, (B) TNF-α, (C) IL-6, (D) MDA, (E) ROS and (F) GSH were determined by ELISA. Different letters in the same column indicate a significant difference (p < 0.05) (n = 6).
FIGURE 7
FIGURE 7
Immunohistochemical staining sections of Bax, bcl-2, Caspase-3 and PI3K in mouse tumor tissues (A) and their expression results (B).
FIGURE 8
FIGURE 8
Expression of mTOR (A), Beclin-1 (B), ULK1 (C) and quantitative analysis (D) in mouse tumor tissues. a–f The different letters denote statistically significant differences (p < 0.05) in the data’s mean values between the ex-perimental groups (n = 3).
FIGURE 9
FIGURE 9
Expression of Ki67 (A) and quantitative analysis (B) in mouse tumor tissues. a–d The different letters denote statistically significant differences (p < 0.05) in the data’s mean values between the experimental groups (n = 3).
See this image and copyright information in PMC

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