{"data":{"id":"10.6084/m9.figshare.33095084.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.33095084.v1","prefix":"10.6084","suffix":"m9.figshare.33095084.v1","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":"Pharmacology"},{"subject":"Chemical Sciences not elsewhere classified"},{"subject":"Immunology"},{"subject":"Cancer"},{"subject":"Infectious Diseases"}],"contributors":[],"dates":[{"date":"2026-07-27","dateType":"Created"},{"date":"2026-08-10","dateType":"Updated"},{"date":"2026-07-27","dateType":"Issued"}],"language":null,"types":{"ris":"JOUR","bibtex":"article","citeproc":"article-journal","schemaOrg":"ScholarlyArticle","resourceType":"Journal contribution","resourceTypeGeneral":"JournalArticle"},"relatedIdentifiers":[{"relationType":"IsPreviousVersionOf","relatedIdentifier":"10.6084/m9.figshare.33095084","relatedIdentifierType":"DOI"},{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/1061186x.2026.2704903","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["715835 Bytes"],"formats":[],"version":"1","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 one of the most difficult malignancies to treat owing to high relapse, enrichment of cancer stem cells (CSCs), and constitutive activation of pro-survival signaling such as NF-κB. We conceived a new therapeutic concept—A Priori Activation of Apoptosis Pathways (AAAPT)—designed to pre-empt and circumvent tumor tactics that desensitize cells to diverse interventions by restoring apoptotic checkpoints while suppressing dysregulated survival pathways (e.g., NF-κB) that are upregulated in resistant clones. CSCs and therapy-refractory TNBC subpopulations overexpress Cathepsin B and exhibit organelle fragility in lysosomes and mitochondria. To target these liabilities, we designed Cathepsin B–cleavable vitamin E analogs (AAAPT leading drugs: AMP-001/002/003) that selectively release active agents inside tumor and CSC populations. In vitro, AMP-001/002/003 showed selective cytotoxicity toward Cathepsin B–positive TNBC cells, inhibited mammosphere formation (a functional surrogate for CSC self-renewal), and spared non-malignant epithelial cells and human iPSC-derived cardiomyocytes. Combination studies revealed strong synergy with doxorubicin, lowering its effective IC\u003csub\u003e50\u003c/sub\u003e. In vivo, AMP-001 significantly reduced TNBC xenograft burden without overt systemic or cardiac toxicity, consistent with the in-vitro safety profile. These findings support Cathepsin B–activated vitamin E analogs as tumor-selective chemosensitizers that address key TNBC liabilities—CSCs, NF-κB–mediated resistance, and organelle-level stress responses—while mitigating doxorubicin-associated cardiotoxicity.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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