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dc.contributor.authorAlnuqaydan, Abdullah M
dc.contributor.authorRah, Bilal
dc.contributor.authorAlmutary, Abdulmajeed G
dc.contributor.authorChauhan, Shailender Singh
dc.date.accessioned2020-06-18T22:26:24Z
dc.date.available2020-06-18T22:26:24Z
dc.date.issued2020-03-01
dc.identifier.citationAlnuqaydan, A. M., Rah, B., Almutary, A. G., & Chauhan, S. S. (2020). Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells. American journal of cancer research, 10(3), 799–815.en_US
dc.identifier.issn2156-6976
dc.identifier.pmid32266092
dc.identifier.urihttp://hdl.handle.net/10150/641651
dc.description.abstractThe development of chemo-resistance against 5-fluorouracil (5-FU) in tumor cells is one of the main debacles in colorectal cancer (CRC) patients. A recent combination of 5-FU with oxaliplatin or cetuximab drastically improves the survival rate in CRC patients; however, the toxicity issue cannot be evaded completely. Thus, searching for novel drug combinations with high specificity and low toxicity is seemingly important. Owing to the less undesirable effects of natural products on normal cells, here we investigated the synergistic antitumor effect of withaferin-A (WA) in combination with 5-FU. Our results demonstrate that the combination of WA and 5-FU induces a significant antiproliferative effect and modulates endoplasmic reticulum (ER) stress in favor of cell death in colorectal cancer (CRC) cells. Mechanistically, the combination upregulates the expression of ER stress sensors (BiP, PERK, CHOP, ATF-4, and eIF2α) and executes PERK axis mediated apoptosis in CRC cells. Additionally, the combined treatment of WA and 5-FU mediated ER stress induces autophagy and apoptosis, which were confirmed by immunoblotting, acridine orange (AO) staining and annexin-V FITC by flow cytometry. In contrast, inhibition of ER stress with salubrinal significantly decreases both autophagic and apoptotic cell populations. Moreover, pharmacological inhibition of either autophagy or apoptosis by their respective inhibitors 3-methyladenine (3-MA) or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methyl ketone (Z-VAD-FMK) decreases their respective population of cells but could not affect either of the population significantly. Finally, the combination attenuates the expression of β-catenin pathway associated proteins and arrests cell cycle at the G2M phase in CRC cells. In summary, the combination of WA and 5-FU decreases cell viability by inducing ER stress-mediated induction of autophagy and apoptosis, inhibiting the β-catenin pathway and arresting the cell cycle at a G2M phase in CRC cells.en_US
dc.language.isoenen_US
dc.publisherE-CENTURY PUBLISHING CORPen_US
dc.rightsAJCR Copyright © 2020. Licensed under CC BY-NC 4.0.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en_US
dc.subjectSynergistic effecten_US
dc.subjectAPOPTOSISen_US
dc.subjectAutophagyen_US
dc.subjectcolorectal canceren_US
dc.subjectendoplasmic reticulumen_US
dc.titleSynergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cellsen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden_US
dc.identifier.journalAMERICAN JOURNAL OF CANCER RESEARCHen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleAmerican journal of cancer research
dc.source.volume10
dc.source.issue3
dc.source.beginpage799
dc.source.endpage815
refterms.dateFOA2020-06-18T22:26:27Z
dc.source.countryUnited States


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AJCR Copyright © 2020. Licensed under CC BY-NC 4.0.
Except where otherwise noted, this item's license is described as AJCR Copyright © 2020. Licensed under CC BY-NC 4.0.