Synthesis of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study

Article

作者: Wu, Wenhui ; Sheng, Ruilong ; Wang, Enxiao ; Ding, Yuxin ; Zhang, Chaoyan ; Guo, Ruihua ; Xing, Lin

Isosteviol is a tetracyclic diterpenoid from the hydrolysis of steviosidic acid, it exhibits a moderate inhibitory impact on tumor proliferation across various cancer types. Herein, we improved antitumor efficacy of isosteviol by modifying its reactive groups at C-16 and C-19 positions. A series of isosteviol derivatives 2-17, were synthesized and characterized. Their anti-proliferative activities were evaluated in three human cancer cell lines (HCT116, SKOV3 and HepG2) by CCK-8 assay. The results showed that derivative 10 has strong cancer cell inhibitory activities (with IC₅₀ = 24.98 ± 1.82 μM for HCT116, IC₅₀ = 26.15 ± 0.05 μM for SKOV3 and IC₅₀ = 23.09 ± 0.31 μM for HepG2 cells). Accordingly, structure-activity relationships (SARs) of these isosteviol derivatives in ovarian cancer SKOV3 cells were discussed in detail. Moreover, derivative 10 has concentration-dependent cell cycle arrest at S-G2/M phases in SKOV3 cells, and it could greatly induce apoptosis. In addition, the targets of isosteviol against ovarian cancer were predicted and analyzed via network pharmacology. Then, molecular docking analysis showed that derivative 10 could interact with HSP90AA1 through its LYS-58 residues (docking energy: -8.96 kal/mol). The results suggested that derivative 10 might be employed as a promising drug candidate for anticancer chemotherapy.

2025-07-08·ACS Nano

Chemical Construction of In Situ Tumor Vaccination.

Review

作者: Xu, Pei ; Wang, Yangyun ; Zhang, Leshuai W ; Cheng, Xiaju ; Wang, Yong

Tumor immunotherapy represents a paradigm shift in cancer treatment, leveraging the body's immune system to recognize and eradicate malignant cells. Among various strategies, in situ tumor vaccination (ISV) has emerged as a promising approach due to its potential for personalization and long-lasting antitumor effects. Despite its advantages, ISV faces significant challenges, including the heterogeneity of the tumor microenvironment, immunosuppressive factors, and antigen loss, which hinder its effectiveness. Innovative chemical construction techniques offer solutions to these challenges by utilizing functionalized platforms that enhance antigen capture, optimize delivery, and facilitate immune activation. By incorporating smart, responsive mechanisms, these platforms can adapt to the tumor microenvironment, improving the stability and release of immune adjuvants. This review explores the integration of chemical strategies in ISV, demonstrating how they can enhance the efficacy of tumor immunotherapy, promote personalized treatment, and address the limitations currently faced in clinical applications.

2025-05-01·JOURNAL OF ETHNOPHARMACOLOGY

Astragali radix - Curcumae rhizoma herb pair suppresses hepatocellular carcinoma through EGFR/AKT/mTOR pathway and induces lipid peroxidation-related ferroptosis via HIF-1α/HO-1/GPX4 axis

Article

作者: Zhu, Zhi-Hui ; Sun, Yu-Mei ; Lu, Jun ; Hu, Hong-Tao ; Shi, Chen-Hao ; Zhao, Hua-Jun ; Wang, Chen ; Gao, Hang ; Bai, Hao-Yang ; An, Hai ; Lu, Jia-Hui

ETHNOPHARMACOLOGICAL RELEVANCE:

The Astragali Radix - Curcumae Rhizoma herb pair (ACHP) originated from the famous traditional Chinese medicine text "YiXueZhongZhongCanXiLu", in which the two herbs were paired to form Chinese herbal compounds commonly used clinically for digestive system tumors, such as hepatocellular carcinoma (HCC). Although ACHP has been inherited for thousands of years in China, its mechanism against HCC remains unclear.

AIM OF THE STUDY:

The study aims to evaluate the effect and explore the mechanism of ACHP against HCC.

METHODS:

The efficacy and safety of ACHP against HCC in vivo were evaluated by tumor volume, organ index, H&E staining, hepatic and renal factors. The serum metabolites of ACHP were identified by UPLC-Q-TOF-MS/MS. The key targets and potential mechanisms of ACHP against HCC were screened by transcriptomics, network pharmacology and molecular docking. The effect and induction of ferroptosis of ACHP-containing serum on HCC in vitro was evaluated by MTT, colony formation assay and specific detection kits. The expression of ferroptosis-related proteins and pathways in vivo was detected by immunohistochemistry.

RESULTS:

ACHP significantly inhibited tumor proliferation compared to the two herbs used separately, and showed a favorable safety profile. A total of 75 serum metabolites were identified in both positive and negative ion modes. Transcriptomics results revealed that ferroptosis played a key role in the anti-HCC process of ACHP. Network pharmacology and molecular docking results suggested that the anti-HCC effect of ACHP may be related to EGFR/AKT/mTOR pathway and HIF-1α/HO-1/GPX4 axis. In vitro and in vivo experiments further demonstrated that ACHP suppressed oncogenic signaling via the EGFR/AKT/mTOR pathway while inducing lipid peroxidation-related ferroptosis through HIF-1α/HO-1/GPX4 axis, thereby inhibiting HepG2 cells proliferation and HCC mice tumor growth.

CONCLUSION:

ACHP exerts its effects by suppressing oncogenic signaling through the EGFR/AKT/mTOR pathway and inducing lipid peroxidation-related ferroptosis in HCC via the HIF-1α/HO-1/GPX4 axis. This systematic investigation establishes a coherent pharmacological chain from compound identification to mechanism verification, highlighting ACHP's therapeutic potential as a ferroptosis inducer targeting oncogenic signaling networks in HCC.

100 项与异甜菊醇相关的药物交易

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