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.contributor.funder	Health Research Board
dc.contributor.funder	Breakthrough Cancer Research, Ireland
dc.date.accessioned	2016-02-17T10:07:56Z
dc.date.available	2016-02-17T10:07:56Z
dc.date.issued	2015
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.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.articleid	e0134676
dc.identifier.doi	10.1371/journal.pone.0134676
dc.identifier.issn	1932-6203
dc.identifier.issued	8	en
dc.identifier.journaltitle	PLOS ONE	en
dc.identifier.uri	https://hdl.handle.net/10468/2299
dc.identifier.volume	10	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

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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