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Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182433/ https://www.ncbi.nlm.nih.gov/pubmed/25268357 http://dx.doi.org/10.1371/journal.pone.0107876 |
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author | Zhou, Tao Ye, Lili Bai, Yu Sun, Aiming Cox, Bryan Liu, Dahai Li, Yong Liotta, Dennis Snyder, James P. Fu, Haian Huang, Bei |
author_facet | Zhou, Tao Ye, Lili Bai, Yu Sun, Aiming Cox, Bryan Liu, Dahai Li, Yong Liotta, Dennis Snyder, James P. Fu, Haian Huang, Bei |
author_sort | Zhou, Tao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4182433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41824332014-10-07 Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog Zhou, Tao Ye, Lili Bai, Yu Sun, Aiming Cox, Bryan Liu, Dahai Li, Yong Liotta, Dennis Snyder, James P. Fu, Haian Huang, Bei PLoS One Research Article 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. Public Library of Science 2014-09-30 /pmc/articles/PMC4182433/ /pubmed/25268357 http://dx.doi.org/10.1371/journal.pone.0107876 Text en © 2014 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Zhou, Tao Ye, Lili Bai, Yu Sun, Aiming Cox, Bryan Liu, Dahai Li, Yong Liotta, Dennis Snyder, James P. Fu, Haian Huang, Bei Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title | Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title_full | Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title_fullStr | Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title_full_unstemmed | Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title_short | Autophagy and Apoptosis in Hepatocellular Carcinoma Induced by EF25-(GSH)(2): A Novel Curcumin Analog |
title_sort | autophagy and apoptosis in hepatocellular carcinoma induced by ef25-(gsh)(2): a novel curcumin analog |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182433/ https://www.ncbi.nlm.nih.gov/pubmed/25268357 http://dx.doi.org/10.1371/journal.pone.0107876 |
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