Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase

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dc.contributor.authorCoulibaly, Safiatou Ten_ZA
dc.contributor.authorRossolillo, Paolaen_ZA
dc.contributor.authorWinter, Floreen_ZA
dc.contributor.authorKretzschmar, Franziska Ken_ZA
dc.contributor.authorBrayé, Mélanieen_ZA
dc.contributor.authorMartin, Darren Pen_ZA
dc.contributor.authorLener, Danielaen_ZA
dc.contributor.authorNegroni, Matteoen_ZA
dc.date.accessioned2016-01-02T05:05:47Z
dc.date.available2016-01-02T05:05:47Z
dc.date.issued2015en_ZA
dc.description.abstractIdentifying enzymes that, once introduced in cancer cells, lead to an increased efficiency of treatment constitutes an important goal for biomedical applications. Using an original procedure whereby mutant genes are generated based on the use of conditional lentivector genome mobilisation, we recently described, for the first time, the identification of a human deoxycytidine kinase (dCK) mutant (G12) that sensitises a panel of cancer cell lines to treatment with the dCK analogue gemcitabine. Here, starting from the G12 variant itself, we generated a new library and identified a mutant (M36) that triggers even greater sensitisation to gemcitabine than G12. With respect to G12, M36 presents an additional mutation located in the region that constitutes the interface of the dCK dimer. The simple presence of this mutation halves both the IC50 and the proportion of residual cells resistant to the treatment. Furthermore, the use of vectors with self-inactivating LTRs leads to an increased sensitivity to treatment, a result compatible with a relief of the transcriptional interference exerted by the U3 promoter on the internal promoter that drives the expression of M36. Importantly, a remarkable effect is also observed in treatments with the anticancer compound cytarabine (AraC), for which a 10,000 fold decrease in IC50 occurred. By triggering the sensitisation of various cancer cell types with poor prognosis to two commonly used anticancer compounds M36 is a promising candidate for suicide gene approaches.en_ZA
dc.identifier.apacitationCoulibaly, S. T., Rossolillo, P., Winter, F., Kretzschmar, F. K., Brayé, M., Martin, D. P., ... Negroni, M. (2015). Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase. <i>PLoS One</i>, http://hdl.handle.net/11427/16161en_ZA
dc.identifier.chicagocitationCoulibaly, Safiatou T, Paola Rossolillo, Flore Winter, Franziska K Kretzschmar, Mélanie Brayé, Darren P Martin, Daniela Lener, and Matteo Negroni "Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase." <i>PLoS One</i> (2015) http://hdl.handle.net/11427/16161en_ZA
dc.identifier.citationCoulibaly, S. T., Rossolillo, P., Winter, F., Kretzschmar, F. K., Brayé, M., Martin, D. P., ... & Negroni, M. (2015). Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase. PloS one, 10(10), e0140741. doi:10.1371/journal.pone.0140741en_ZA
dc.identifier.ris TY - Journal Article AU - Coulibaly, Safiatou T AU - Rossolillo, Paola AU - Winter, Flore AU - Kretzschmar, Franziska K AU - Brayé, Mélanie AU - Martin, Darren P AU - Lener, Daniela AU - Negroni, Matteo AB - Identifying enzymes that, once introduced in cancer cells, lead to an increased efficiency of treatment constitutes an important goal for biomedical applications. Using an original procedure whereby mutant genes are generated based on the use of conditional lentivector genome mobilisation, we recently described, for the first time, the identification of a human deoxycytidine kinase (dCK) mutant (G12) that sensitises a panel of cancer cell lines to treatment with the dCK analogue gemcitabine. Here, starting from the G12 variant itself, we generated a new library and identified a mutant (M36) that triggers even greater sensitisation to gemcitabine than G12. With respect to G12, M36 presents an additional mutation located in the region that constitutes the interface of the dCK dimer. The simple presence of this mutation halves both the IC50 and the proportion of residual cells resistant to the treatment. Furthermore, the use of vectors with self-inactivating LTRs leads to an increased sensitivity to treatment, a result compatible with a relief of the transcriptional interference exerted by the U3 promoter on the internal promoter that drives the expression of M36. Importantly, a remarkable effect is also observed in treatments with the anticancer compound cytarabine (AraC), for which a 10,000 fold decrease in IC50 occurred. By triggering the sensitisation of various cancer cell types with poor prognosis to two commonly used anticancer compounds M36 is a promising candidate for suicide gene approaches. DA - 2015 DB - OpenUCT DO - 10.1371/journal.pone.0140741 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase TI - Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase UR - http://hdl.handle.net/11427/16161 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16161
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0140741
dc.identifier.vancouvercitationCoulibaly ST, Rossolillo P, Winter F, Kretzschmar FK, Brayé M, Martin DP, et al. Potent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinase. PLoS One. 2015; http://hdl.handle.net/11427/16161.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis 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.rights.holder© 2015 Coulibaly et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherCloningen_ZA
dc.subject.otherPhosphorylationen_ZA
dc.subject.otherCancer treatmenten_ZA
dc.subject.other293T cellsen_ZA
dc.subject.otherLibrary screeningen_ZA
dc.subject.otherPoint mutationen_ZA
dc.subject.otherPlasmid constructionen_ZA
dc.subject.otherSubstitution mutationen_ZA
dc.titlePotent sensitisation of cancer cells to anticancer drugs by a quadruple mutant of the human deoxycytidine kinaseen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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