Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues.

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dc.citation.doi10.1371/journal.pone.0138607.en_ZA
dc.citation.issue9en_ZA
dc.contributor.authorHarmse, L.
dc.contributor.authorDahan-Farkas, N.
dc.contributor.authorPanayides, J.L.
dc.contributor.authorVan Otterlo, W.
dc.contributor.authorPenny, C.
dc.date.accessioned2016-10-17T13:42:16Z
dc.date.available2016-10-17T13:42:16Z
dc.date.issued2015-09-21
dc.description.abstractDespite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.en_ZA
dc.description.librarianNCS2016.en_ZA
dc.description.sponsorshipThis work was supported by the Research Niche Areas Program of the National Research Foundation (NRF) of South Africa and the University of the Witwatersrand Faculty of Health Sciences Research Committee.en_ZA
dc.identifier.citationHarmse,L.et al. 2015.Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues.PLoS ONE 10 (9): e0138607.en_ZA
dc.identifier.issn1932-6203.
dc.identifier.urihttp://hdl.handle.net/10539/21231
dc.journal.titlePLoS ONE.en_ZA
dc.journal.volume10en_ZA
dc.language.isoenen_ZA
dc.publisherPublic Library of Science.en_ZA
dc.rights© 2015 Harmse 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_ZA
dc.subject5' (4,4 dimethoxytrityl)uridineen_ZA
dc.subject5' tert butyldiphenylsilylcytidineen_ZA
dc.subject5' tert butyldiphenylsilyluridineen_ZA
dc.subjectactinen_ZA
dc.subjectantineoplastic agenten_ZA
dc.subjectcamptothecinen_ZA
dc.subjectcaspase 3en_ZA
dc.subjectcaspase 8en_ZA
dc.subjectcaspase 9en_ZA
dc.subjectchloroquineen_ZA
dc.titleAberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues.en_ZA
dc.typeArticleen_ZA
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