{"doi":"10.1016/j.phymed.2024.156344","title":"Tetramethylpyrazine attenuates the cancer stem cell like-properties and doxorubicin resistance by targeting HMGCR in breast cancer","abstract":null,"journal":"Phytomedicine","year":2025,"id":616247,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":890220,"name":"Manli Wang","orcid":"0000-0001-8701-3530","position":1,"is_corresponding":false},{"id":350971,"name":"Guoliang Cui","orcid":"0000-0001-5559-7957","position":2,"is_corresponding":false},{"id":1425019,"name":"Yuanyuan Wu","orcid":"0000-0001-6262-1513","position":3,"is_corresponding":false},{"id":1588699,"name":"Zhonghong Wei","orcid":null,"position":4,"is_corresponding":false},{"id":1588703,"name":"Suyun Yu","orcid":null,"position":5,"is_corresponding":false},{"id":1588706,"name":"Aiyun Wang","orcid":null,"position":6,"is_corresponding":false},{"id":1244119,"name":"Wei Zou","orcid":"0000-0002-8116-1046","position":7,"is_corresponding":false},{"id":1588709,"name":"Yanhong Pan","orcid":"0000-0003-1734-4670","position":8,"is_corresponding":false},{"id":212504,"name":"Xiaoman Li","orcid":null,"position":9,"is_corresponding":false},{"id":370684,"name":"Yin Lu","orcid":"0000-0003-2063-8485","position":10,"is_corresponding":false},{"id":844367,"name":"Xuan Jiang","orcid":"0000-0001-7802-0165","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Tetramethylpyrazine attenuates the cancer stem cell like-properties and doxorubicin resistance by targeting HMGCR in breast cancer","abstract":"<h4>Background</h4>Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat, has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood.<h4>Purpose</h4>Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics.<h4>Methods</h4>Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo, extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7<sup>ADR</sup>) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed.<h4>Results</h4>TMP was found to inhibit BCSC-like properties both in vitro and in vivo, evidenced by a reduction in the CD44<sup>+</sup>/CD24<sup>-</sup> population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR.<h4>Conclusion</h4>These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39729781","pmcid":null,"openalex_id":"https://openalex.org/W4405808459","authors":[],"funders":[],"total_grants":0,"fwci":0.5487,"citation_percentile":0.69976366,"influential_citations":0,"citation_trend":[{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://doi.org/10.1016/j.phymed.2024.156344","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39729781","host_type":"repository"}],"fields_of_study":["Drug Transport and Resistance Mechanisms","Cancer, Lipids, and Metabolism","Ferroptosis and cancer prognosis","Neoplastic Stem Cells","Humans","Breast Neoplasms","Drug Resistance, Neoplasm","Doxorubicin","Female","Pyrazines","Hydroxymethylglutaryl CoA Reductases","Animals","Cell Line, Tumor","Mice","MCF-7 Cells","Drug Resistance, Multiple"],"mesh_terms":["Animals","Breast Neoplasms","Doxorubicin","Female","Humans","Hydroxymethylglutaryl CoA Reductases","Pyrazines","Neoplastic Stem Cells","Drug Resistance, Multiple","Drug Resistance, Neoplasm","Cell Line, Tumor","Mice","MCF-7 Cells"],"keywords":["Tetramethylpyrazine","Doxorubicin","Cancer research","Breast cancer","Abcg2","Cancer","Medicine","Cancer stem cell","Pharmacology","Chemistry","Internal medicine","Transporter","ATP-binding cassette transporter","Chemotherapy","Pathology","Biochemistry","Gene","Drug resistance","Cancer Stem Cells","Hmgcr"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T22:23:47.030228Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}