期刊
PLOS ONE
卷 9, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0107876
关键词
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资金
- Natural Science Foundation of the Education Department in Anhui Province, China [KJ2012A030]
- NCI SPORE in Head and Neck Cancer [5 P50 CA128613]
Curcumin, a spice component as well as a traditional Asian medicine, has been reported to inhibit proliferation of a variety of cancer cells but is limited in application due to its low potency and bioavailability. Here, we have assessed the therapeutic effects of a novel and water soluble curcumin analog, 3,5-bis(2-hydroxybenzylidene) tetrahydro-4H-pyran-4-one glutathione conjugate [EF25-(GSH)(2)], on hepatoma cells. Using the MTT and colony formation assays, we determined that EF25-(GSH)(2) drastically inhibits the proliferation of hepatoma cell line HepG2 with minimal cytotoxicity for the immortalized human hepatic cell line HL-7702. Significantly, EF25-(GSH)(2) suppressed growth of HepG2 xenografts in mice with no observed toxicity to the animals. Mechanistic investigation revealed that EF25-(GSH)(2) induces autophagy by means of a biphasic mechanism. Low concentrations (<5 mu mol/L) induced autophagy with reversible and moderate cytoplasmic vacuolization, while high concentrations (> 10 mu mol/L) triggered an arrested autophagy process with irreversible and extensive cytoplasmic vacuolization. Prolonged treatment with EF25-(GSH)(2) induced cell death through both an apoptosis-dependent and a non-apoptotic mechanism. Chloroquine, a late stage inhibitor of autophagy which promoted cytoplasmic vacuolization, led to significantly enhanced apoptosis and cytotoxicity when combined with EF25-(GSH)(2). Taken together, these data imply a fail-safe mechanism regulated by autophagy in the action of EF25-(GSH)(2), suggesting the therapeutic potential of the novel curcumin analog against hepatocellular carcinoma (HCC), while offering a novel and effective combination strategy with chloroquine for the treatment of patients with HCC.
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