title: Autophagy and apoptosis in hepatocellular carcinoma induced by EF25-(GSH)2: a novel curcumin analog.
abstract: 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 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.
authors.affiliation: School of life Sciences, Anhui University, Hefei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: School of life Sciences, Anhui University, Hefei, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Ye
authors.affiliation: School of life Sciences, Anhui University, Hefei, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia, United States of America; Emory Institute for Drug Development (EIDD), Emory University, Atlanta, Georgia, United States of America.
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Cox
authors.affiliation: School of life Sciences, Anhui University, Hefei, China; Center for Stem Cell and Translational Medicine, Anhui University, Hefei, China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of life Sciences, Anhui University, Hefei, China; Center for Stem Cell and Translational Medicine, Anhui University, Hefei, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia, United States of America; Emory Institute for Drug Development (EIDD), Emory University, Atlanta, Georgia, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Liotta
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia, United States of America; Emory Institute for Drug Development (EIDD), Emory University, Atlanta, Georgia, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: School of life Sciences, Anhui University, Hefei, China; Center for Stem Cell and Translational Medicine, Anhui University, Hefei, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Huang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
chemical_list: C502778:ATG5 protein, human; D000730:Androstadienes; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; C000598849:EF25-(GSH)2; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D003474:Curcumin; D000077191:Wortmannin