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Mechanistic Insights into Xihuang Wan against Bladder Cancer via PI3K/ AKT/BCL2-Mediated Apoptosis Inhibition:
Jing Li1, Shun Zhang1, Shenggen Yu1
1Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Introduction:
Bladder cancer (Blca) is highly recurrent with limited options for advanced disease, and the pharmacological basis of traditional Chinese medicine formulas such as Xihuang Wan (XHW) in Blca is poorly defined. This study investigated the anti-bladder cancer mechanism of XHW by identifying its core bioactive component and its modulation of PI3K/AKT/BCL2-mediated apoptosis.
Methods:
Network pharmacology integrated TCMSP/SymMap and GeneCards/OMIM to identify active ingredients, Blca targets, and enriched pathways. Molecular docking and 100-ns molecular dynamics simulations evaluated the binding of the core component quercetin to key targets. CCK-8 and Western blot assays assessed XHW cytotoxicity, PI3K-AKT signaling, and apoptosis-related proteins in MB49 cells. Antitumor efficacy was confirmed in a C57BL/6 mouse MB49 subcutaneous xenograft model.
Results:
We identified 110 common targets and highlighted quercetin as a central ingredient acting on AKT1 and BCL2. KEGG analysis implicated the PI3K-AKT pathway, and docking/simulations supported stable quercetin binding. XHW inhibited MB49 proliferation and suppressed tumor growth in vivo. XHW, similar to Wortmannin, reduced phosphorylated AKT, increased the Bax/Bcl-2 ratio, and elevated cleaved caspase-3, indicating mitochondrial apoptosis via PI3K-AKT inhibition.
Discussion:
These findings indicate that XHW acts partly through functional inhibition of the PI3K/ AKT/BCL2 axis rather than nonspecific cytotoxicity.
Conclusion:
Xihuang Wan exerts anti-bladder cancer activity mainly through quercetin targeting the PI3K/AKT/BCL2 axis to inhibit tumor cell survival and trigger mitochondrial apoptosis, supporting further development of XHW and quercetin as adjunctive strategies for bladder cancer.
Insights
Xihuang Wan (XHW) combats bladder cancer by inhibiting the PI3K/AKT/BCL2 pathway. Its active component, quercetin, triggers apoptosis, offering a potential adjunctive therapy for bladder cancer.
Area of Science:
- Oncology
- Pharmacology
- Traditional Chinese Medicine
Background:
- Bladder cancer (Blca) is a recurrent malignancy with limited advanced treatment options.
- The precise pharmacological mechanisms of traditional Chinese medicine formulas, like Xihuang Wan (XHW), in Blca remain underexplored.
- Investigating XHW's anti-cancer effects can reveal novel therapeutic strategies.
Purpose of the Study:
- To elucidate the anti-bladder cancer mechanism of Xihuang Wan (XHW).
- To identify the core bioactive component of XHW responsible for its anti-cancer effects.
- To determine how XHW modulates the PI3K/AKT/BCL2 signaling pathway and induces apoptosis in bladder cancer cells.
Main Methods:
- Network pharmacology integrated multiple databases (TCMSP/SymMap, GeneCards/OMIM) to identify XHW's active ingredients and bladder cancer targets.
- Molecular docking and simulations assessed the binding affinity of quercetin to key targets.
- In vitro (MB49 cells) and in vivo (mouse xenograft model) experiments evaluated XHW's efficacy and mechanism of action.
Main Results:
- Quercetin was identified as a central active component of XHW, targeting AKT1 and BCL2.
- KEGG pathway analysis revealed the PI3K-AKT pathway as a key target, with molecular simulations confirming stable quercetin binding.
- XHW demonstrated significant inhibition of MB49 cell proliferation and suppressed tumor growth in vivo, inducing mitochondrial apoptosis via PI3K-AKT pathway inhibition.
Conclusions:
- Xihuang Wan (XHW) exhibits anti-bladder cancer activity primarily through its component quercetin.
- Quercetin targets the PI3K/AKT/BCL2 axis, inhibiting tumor cell survival and promoting mitochondrial apoptosis.
- XHW and quercetin show promise as adjunctive therapeutic strategies for bladder cancer treatment.
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