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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-4 H -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 µmol/L) induced autophagy with reversible and moderate cytoplasmic vacuolization, while high concentrations (>10 µmol/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.

Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)2: A Novel Curcumin Analog