{"data":{"id":"10.6084/m9.figshare.33095084","type":"dois","attributes":{"doi":"10.6084/m9.figshare.33095084","prefix":"10.6084","suffix":"m9.figshare.33095084","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Raghu Pandurangi","givenName":"Raghu","familyName":"Pandurangi","affiliation":[],"nameIdentifiers":[]},{"name":"Marco Tomasetti","givenName":"Marco","familyName":"Tomasetti","affiliation":[],"nameIdentifiers":[]},{"name":"Sekar T. Verapazham","givenName":"Sekar T.","familyName":"Verapazham","affiliation":[],"nameIdentifiers":[]},{"name":"Ramasamy Paulmurugan","givenName":"Ramasamy","familyName":"Paulmurugan","affiliation":[],"nameIdentifiers":[]},{"name":"Cynthia Ma","givenName":"Cynthia","familyName":"Ma","affiliation":[],"nameIdentifiers":[]},{"name":"Sandeep Rajput","givenName":"Sandeep","familyName":"Rajput","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Cathepsin B-activated vitamin E prodrugs target cancer stem cells and enhance chemotherapy response in triple-negative breast cancer with minimal cardiotoxicity"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2026,"subjects":[{"subject":"Biochemistry"},{"subject":"Medicine"},{"subject":"Cell Biology"},{"subject":"Molecular Biology"},{"subject":"Neuroscience"},{"subject":"Pharmacology"},{"subject":"Biotechnology"},{"subject":"Biological Sciences not elsewhere classified"},{"subject":"Cancer"}],"contributors":[],"dates":[{"date":"2026-08-10","dateType":"Created"},{"date":"2026-08-10","dateType":"Updated"},{"date":"2026-08-10","dateType":"Issued"}],"language":null,"types":{"ris":"JOUR","bibtex":"article","citeproc":"article-journal","schemaOrg":"ScholarlyArticle","resourceType":"Journal contribution","resourceTypeGeneral":"JournalArticle"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/1061186x.2026.2704903","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["715835 Bytes"],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"Triple-negative breast cancer (TNBC) remains difficult to treat because of therapeutic resistance, cancer stem cell (CSC) enrichment, and constitutive NF-κB activation. We developed a new therapeutic strategy, A Priori Activation of Apoptosis Pathways (AAAPT), to restore apoptotic competence before chemotherapy by suppressing survival signaling and reactivating programmed cell death. Since TNBC and CSC-enriched populations overexpress Cathepsin B and exhibit lysosomal and mitochondrial vulnerabilities, we designed Cathepsin B-cleavable vitamin E analogues (AMP-001/002/003) that selectively release the active pharmacophore within tumor cells. AMP-001/002/003 demonstrated selective cytotoxicity toward Cathepsin B-positive TNBC cells, inhibited mammosphere formation, and spared normal epithelial cells and human iPSC-derived cardiomyocytes. AMP-001 synergized strongly with doxorubicin, markedly reducing its effective IC₅。 while restoring chemosensitivity. In TNBC xenograft models, AMP-001 significantly reduced tumor burden without overt systemic or cardiac toxicity. Collectively, these findings establish AAAPT as a tumor-selective chemosensitization platform that targets CSCs, reverses NF-κB-mediated resistance, exploits lysosomal–mitochondrial vulnerabilities, and expands the therapeutic index of doxorubicin by maintaining antitumor efficacy while reducing cardiotoxicity.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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