Mitochondria-targeting drug oligomycin blocked P-glycoprotein activity and triggered apoptosis in doxorubicin-resistant HepG2 cells.
Chemotherapy, 2004/6;50(2):55-62.
Li YC[1], Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK
Affiliations
PMID: 15211078
Impact factor: 3.549
Abstract
background: Mitochondria are key regulators in apoptosis. This suggests that a mitochondrion can be a target for cancer treatment. To examine the feasibility of this approach, we investigated the effect of oligomycin on the induction of apoptosis in drug-resistant cells. As a mitochondrion-targeting agent, oligomycin inhibits mitochondrial F0F1-ATPase. Of 37,000 molecules tested against the 60 human cancer cell lines of the National Cancer Institute, oligomycin is among the top 0.1% most cell line selective agents.
methods: Changes in the doxorubicin (Dox) accumulation and mitochondrial potential (Deltapsim) in human hepatocarcinoma HepG2 and its derivative R-HepG2 with Dox resistance were determined by flow cytometry. P-glycoprotein (Pgp) expression and release of cytochrome c from mitochondria were analyzed by Western blot. Cytotoxicity was examined by DNA fragmentation and the alamar blue assay.
results: R-HepG2 cells produced Pgp, showed drug resistance and accumulated less Dox when compared to their parent. In both cell lines, oligomycin depolarized Deltapsim, released cytochrome c and elicited DNA fragmentation. Moreover, oligomycin blocked Pgp activity and accumulated more Dox in R-HepG2. Combined treatment with Dox and oligomycin elicited more cell death.
conclusion: Our results suggest that oligomycin could bypass Dox resistance and trigger apoptosis in R-HepG2 cells.
MeSH terms
ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Doxorubicin; Drug Delivery Systems; Drug Interactions; Drug Resistance, Neoplasm; Humans; Mitochondria, Liver; Oligomycins
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