Lithium modulates autophagy in esophageal and colorectal cancer cells and enhances the efficacy of therapeutic agents in vitro and in vivo

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dc.contributor.author O'Donovan, Tracey R.
dc.contributor.author Rajendran, Simon
dc.contributor.author O'Reilly, Seamus
dc.contributor.author O'Sullivan, Gerald C.
dc.contributor.author McKenna, Sharon L.
dc.date.accessioned 2016-02-17T10:07:56Z
dc.date.available 2016-02-17T10:07:56Z
dc.date.issued 2015
dc.identifier.volume 10 en
dc.identifier.issued 8 en
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10468/2299
dc.identifier.doi 10.1371/journal.pone.0134676
dc.description.abstract Many epithelial cancers, particularly gastrointestinal tract cancers, remain poor prognosis diseases, due to resistance to cytotoxic therapy and local or metastatic recurrence. We have previously shown that apoptosis incompetent esophageal cancer cells induce autophagy in response to chemotherapeutic agents and this can facilitate their recovery. However, known pharmacological inhibitors of autophagy could not enhance cytotoxicity. In this study, we have examined two well known, clinically approved autophagy inducers, rapamycin and lithium, for their effects on chemosensitivity in apoptosis incompetent cancer cells. Both lithium and rapamycin were shown to induce autophagosomes in esophageal and colorectal cancer cells by western blot analysis of LC3 isoforms, morphology and FACS quantitation of Cyto-ID or mCherry-GFP-LC3. Analysis of autophagic flux indicates inefficient autophagosome processing in lithium treated cells, whereas rapamycin treated cells showed efficient flux. Viability and recovery was assessed by clonogenic assays. When combined with the chemotherapeutic agent 5-fluorouracil, rapamycin was protective. In contrast, lithium showed strong enhancement of non-apoptotic cell death. The combination of lithium with 5-fluorouracil or oxaliplatin was then tested in the syngenic mouse (balb/c) colorectal cancer model-CT26. When either chemotherapeutic agent was combined with lithium a significant reduction in tumor volume was achieved. In addition, survival was dramatically increased in the combination group (p < 0.0001), with > 50% of animals achieving long term cure without re-occurrence (> 1 year tumor free). Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis deficient cancer cells. Induction of compromised autophagy may contribute to this cytotoxicity. en
dc.description.sponsorship Health Research Board (HRA_POR/2011/55) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Public Library of Science en
dc.rights © 2015 O'Donovan et al. 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 credited en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ en
dc.subject Tumor stroma model en
dc.subject Ischemia/reperfusion injury en
dc.subject Membrane permeabilization en
dc.subject Cardiomyocyte death en
dc.subject Oxidative stress en
dc.subject Flow cytometry en
dc.subject Inhibition en
dc.subject Degradation en
dc.subject Growth en
dc.subject Drug en
dc.title Lithium modulates autophagy in esophageal and colorectal cancer cells and enhances the efficacy of therapeutic agents in vitro and in vivo en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Sharon McKenna, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland. +353-21-490-3000 Email: s.mckenna@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.internal.wokid WOS:000359062300058
dc.contributor.funder Health Research Board
dc.contributor.funder Breakthrough Cancer Research, Ireland
dc.description.status Peer reviewed en
dc.identifier.journaltitle PLOS ONE en
dc.internal.IRISemailaddress s.mckenna@ucc.ie en
dc.identifier.articleid e0134676


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© 2015 O'Donovan et al. 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 credited Except where otherwise noted, this item's license is described as © 2015 O'Donovan et al. 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 credited
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