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- W2320173552 abstract "Dimethylaminoparthenolide (DMAPT) is in Phase I trials to treat acute myeloid leukemia (AML) and exhibits specific toxicity for AML stem cells with no reported normal tissue toxicity. Its putative modes of action are inhibition of NFkB and inducing an oxidative stress. This study is a first screen of DMAPT as a potential treatment for HCC. Walker 256 cells (used in rat HCC model), HepG2 cells (human HCC), and normal rat hepatocytes were tested for DMAPT-induced cytotoxicity using the standard, NCI drug toxicity protocol (48 h drug exposure). Measured endpoints included cell counts (Growth Inhibition), release of lactate dehydrogenase (LDH: loss of membrane integrity) and the colony formation assay (CFA). Chemosensitization was tested with doxorubicin (DOX: 1-10 µM) or buthionine sulphoximine (BSO: 5-100 µM). DOX was selected because DMAPT’s NFkB inhibition might potentiate DOX-induced DNA damage while BSO inhibits glutathione (GSH) and might potentiate DMAPT’s oxidative stress. Radiosensitization was tested by quantifying gH2AX foci using flow cytometry following ionizing radiation (5 Gy). GI50 (50% growth inhibition) and LD50 DMAPT doses for Walker 256 cells are respectively, 1.6 µM and 3 µM, and respectively, 3 µM and 13 µM for HepG2 cells. Doses up to 45 µM DMAPT were nontoxic to normal rat hepatocytes. BSO alone was nontoxic, but 10 µM BSO potentiated DMAPT cytotoxicity 6-fold, while 1.5 µM DMAPT potentiated DOX toxicity 10-fold. DMAPT (5-15 µM for 30 min: a nontoxic exposure) inhibited DNA double strand break repair in the tumor cell lines. N-acetyl cysteine (100 µM) diminished DMAPT cytotoxicity and chemosensitization indicating the involvement of an oxidative stress. The tumor cell selectivity of DMAPT cytotoxicity for liver tumor cells suggests that DMAPT may be an effective drug for treating liver tumors when delivered orally, IV, or with tumor embolization. DMAPT’s ability to be potentiated by BSO or to potentiate DOX suggests that adding DMAPT in a TACE regimen could improve efficacy. DMAPT-induced radiosensitization should be investigated further for improving efficacy of radioembolization or external beam radiotherapy of liver tumors." @default.
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- W2320173552 date "2015-02-01" @default.
- W2320173552 modified "2023-09-27" @default.
- W2320173552 title "Dimethyaminoparthenolide exhibits selective toxicity and chemosensitization for liver tumor cells" @default.
- W2320173552 doi "https://doi.org/10.1016/j.jvir.2014.12.051" @default.
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