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

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dc.contributor.author Harmse, L.
dc.contributor.author Dahan-Farkas, N.
dc.contributor.author Panayides, J.L.
dc.contributor.author Van Otterlo, W.
dc.contributor.author Penny, C.
dc.date.accessioned 2016-10-17T13:42:16Z
dc.date.available 2016-10-17T13:42:16Z
dc.date.issued 2015-09-21
dc.identifier.citation Harmse,L.et al. 2015.Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues.PLoS ONE 10 (9): e0138607. en_ZA
dc.identifier.issn 1932-6203.
dc.identifier.uri http://hdl.handle.net/10539/21231
dc.description.abstract Despite 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.sponsorship This 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.language.iso en en_ZA
dc.publisher Public 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.subject 5' (4,4 dimethoxytrityl)uridine en_ZA
dc.subject 5' tert butyldiphenylsilylcytidine en_ZA
dc.subject 5' tert butyldiphenylsilyluridine en_ZA
dc.subject actin en_ZA
dc.subject antineoplastic agent en_ZA
dc.subject camptothecin en_ZA
dc.subject caspase 3 en_ZA
dc.subject caspase 8 en_ZA
dc.subject caspase 9 en_ZA
dc.subject chloroquine en_ZA
dc.title Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues. en_ZA
dc.type Article en_ZA
dc.journal.volume 10 en_ZA
dc.journal.title PLoS ONE. en_ZA
dc.description.librarian NCS2016. en_ZA
dc.citation.doi 10.1371/journal.pone.0138607. en_ZA
dc.citation.issue 9 en_ZA

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