Metabolic fate of the natural anticancer agent cucurbitacin B: an LC-MS/MS-enabled profiling of its major phase I and II conjugates in vivo.

Wen-Ya Liu, Di Xu, Hui-Hui Meng, Cheng-Yao Wang, Xin Feng, Jun-Song Wang

Abstract read

In one paragraph

Article in Analytical and bioanalytical chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

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2citing papers in PubMed

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1 · What the graph read from it

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3 · Its place in the literature

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2 citing papers in PubMed.

4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Wen-Ya Liu *Center of Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.

Di Xu *Center of Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.

Hui-Hui MengCenter of Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.

Cheng-Yao WangCenter of Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.

Xin FengTibetan Medicine Institute, China Tibetology Research Center, Beijing, 100101, China.

Jun-Song WangCenter of Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. wang.junsong@gmail.com.

Funding

National Natural Science Foundation of China 81773857National Natural Science Foundation of China 82104356

6 · The paper itself

Abstract

Cucurbitacin B (CuB) is a natural triterpenoid with diverse pharmacological effects including potent anticancer activity. However, its oral bioavailability is hampered by limited metabolism in vivo. We characterized CuB's in vivo metabolism in rats to uncover bioactive metabolites retaining therapeutic potential, using a robust UHPLC-Q-TOF-MS/MS workflow. This workflow combined molecular networking, fragmentation filtering, and mass defect filtering to identify CuB metabolites in rat urine, plasma, and feces following oral administration. Thirteen metabolites were identified and seven were confirmed. Major phase I transformations involved hydrolysis, reduction, epoxidation, and amination. Phase II conjugation included cysteine, glutathione, glucuronide, and gluconic acid conjugates. Notably, one of the main metabolites formed was the cysteine conjugate CuB-Cys. CuB-Cys maintained similar in vitro antiproliferative activity to CuB on HepG2, MCF-7, and PANC-1 cancer cell lines. However, it demonstrated lower cytotoxicity towards non-cancerous L02 cells, highlighting improved therapeutic selectivity. Mechanistically, CuB-Cys induced greater apoptotic signaling in HepG2 cells than CuB via enhanced caspase activation and disrupted BAX-Bcl-2 balance. This represents the first systematic characterization of CuB's in vivo metabolic pathway. The identification and confirmation of CuB-Cys provide insight for drug development efforts aiming to maintain therapeutic efficacy while reducing toxicity, via metabolite-based approaches. Our findings shed light on strategies for improving CuB's clinical potential.

Indexed as

Antineoplastic AgentsTandem Mass SpectrometryTriterpenesAnimalsApoptosisCell Line, TumorCell ProliferationChromatography, High Pressure LiquidHumansLiquid Chromatography-Mass SpectrometryMaleRatsRats, Sprague-DawleyAntineoplastic Agentscucurbitacin BTriterpenesAntiproliferative activityCucurbitacin BDrug metabolismMetabolite identificationMolecular networkingUHPLC-Q-TOF–MS/MS

Identifiers

PMID39441433

DOI10.3390/cells13020183

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.