{"id":"e8b6bdc2-ad9e-588d-8385-b69555804b59","stable_key":"cea4b417-bb71-5d5d-8fe1-4e175aca750c:graviola-tamoxifen-additivity","predicate":"adds_to","statement":"Annonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"98db4ab7-56e0-5b32-bb22-1d73775171a9","mechanism_event_label":"Annonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.","subject":{"id":"46b657b6-1692-59cb-bccd-e94db35a2734","slug":"annonacin","display_name":"Annonacin","entity_type_key":"small_molecule"},"object":{"id":"9216da1f-63b6-573f-9e30-e4334d3358be","slug":"4-hydroxytamoxifen-mcf7-growth-inhibition","display_name":"4-Hydroxytamoxifen inhibition of MCF-7 cell survival","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"98db4ab7-56e0-5b32-bb22-1d73775171a9","stable_key":"cea4b417-bb71-5d5d-8fe1-4e175aca750c:graviola-tamoxifen-additivity-event","event_type":"observed_relationship","label":"Annonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.","description":"Annonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"46b657b6-1692-59cb-bccd-e94db35a2734","slug":"annonacin","display_name":"Annonacin","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9216da1f-63b6-573f-9e30-e4334d3358be","slug":"4-hydroxytamoxifen-mcf7-growth-inhibition","display_name":"4-Hydroxytamoxifen inhibition of MCF-7 cell survival","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"acac079b-66bd-5db4-a827-39092d9c9dfe","slug":"4-hydroxytamoxifen","display_name":"4-Hydroxytamoxifen","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"c0e29b2d-fd18-5124-ad3d-8e09a4069fd2","slug":"estrogen-receptor-alpha","display_name":"Estrogen receptor alpha / ESR1","entity_type_key":"protein"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"dose","value_text":"Annonacin 0.1-1 micromolar with 4-hydroxytamoxifen 1 micromolar; mouse dosing in primary article","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"duration","value_text":"48 hours in cells; 7-22 days in mice","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_access","value_text":"Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_scope","value_text":"literature_reviewed; model-specific source-derived curation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human MCF-7 cells and nude-mouse xenografts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Additivity in preclinical models is not evidence to combine graviola with tamoxifen; annonacin toxicity and pharmacokinetics remain limiting.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Graviola (Annona muricata) chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings.","comparator":null,"unit":null,"notes":"","entity":{"slug":"graviola","display_name":"Graviola / Annona muricata","entity_type_key":"botanical"}},{"dimension":"organism","value_text":"Human MCF-7 cells and nude-mouse xenografts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Annonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells. (2011). https://pubmed.ncbi.nlm.nih.gov/21840388/ DOI: 10.1016/j.jep.2011.07.056","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"route","value_text":"In vitro and in vivo","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue","value_text":"Cell survival, ER-alpha signaling and xenograft size","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"16113832-d2f9-5c72-8ab0-93a86b50c8ae","evidence_kind":"source_excerpt","locator":"Lines 110-119","start_line":110,"end_line":119,"excerpt":"## graviola-tamoxifen-additivity\nAnnonacin and 4-hydroxytamoxifen additively reduced MCF-7 survival and estrogen-receptor transcriptional activity; annonacin also reduced MCF-7 xenograft growth in nude mice.\nModel/species: Human MCF-7 cells and nude-mouse xenografts\nTissue/system: Cell survival, ER-alpha signaling and xenograft size\nExposure: Annonacin 0.1-1 micromolar with 4-hydroxytamoxifen 1 micromolar; mouse dosing in primary article\nRoute: In vitro and in vivo\nDuration: 48 hours in cells; 7-22 days in mice\nLimits: Additivity in preclinical models is not evidence to combine graviola with tamoxifen; annonacin toxicity and pharmacokinetics remain limiting.\nPrimary reference: Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7 cells. (2011). https://pubmed.ncbi.nlm.nih.gov/21840388/ DOI: 10.1016/j.jep.2011.07.056\nAccess: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.","model_system":"Human MCF-7 cells and nude-mouse xenografts","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Exact original curation span with primary citation; not a publisher quotation.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"dde73deb-4328-5cc7-aa41-04b7d845f4fa","stable_key":"import-cea4b417-bb71-5d5d-8fe1-4e175aca750c","title":"Graviola (Annona muricata): mechanism of action and interactions (2026-09-20)","document_type":"imported_text","citation_label":"Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. 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