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Inhibition of survivin expression after using oxaliplatin and vinflunine to induce cytogenetic damage in vitro in lymphocytes from colon cancer patients and healthy individuals

Alotaibi, Amal AA and Najafzadeh, Mojgan and Davies, Justin D and Baumgartner, Adi and Anderson, Diana (2017) Inhibition of survivin expression after using oxaliplatin and vinflunine to induce cytogenetic damage in vitro in lymphocytes from colon cancer patients and healthy individuals. Mutagenesis, 32 (5). pp. 517-524.

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Abstract

Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin which causes DNA double-strand breaks and vinflunine which disrupts the mitotic spindle are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response. Endpoints examined included micronucleus (MN) induction using the cytokinesis-blocked micronucleus (CBMN) assay and pancentromeric fluorescence in situ hybridisation. Also, survivin expression was monitored since it regulates the mitotic spindle checkpoint and inhibits apoptosis. Oxaliplatin produced cytogenetic damage (MN in binucleated cells) via its clastogenic but also previously unknown aneugenic action, possibly through interfering with topoisomerase II, whilst vinflunine produced MN in mononucleated cells because of incomplete karyokinesis. Survivin expression was found to be significantly reduced in a concentration-dependent manner by not only oxaliplatin but surprisingly also vinflunine. This resulted in large numbers of multinucleated cells found with the CBMN assay. As survivin is upregulated in cancers, eliminating apoptosis inhibition might provide a more targeted chemotherapy approach; particularly, when considering vinflunine, which only affects cycling cells by inhibiting their mitotic spindle, and alongside possibly other pro-apoptotic compounds. Hence, these newly found properties vinflunine – the inhibition of survivin expression - might demonstrate a promising chemotherapeutic approach as vinflunine induces less DNA damage in normal somatic cells compared to other chemotherapeutic compounds.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Mutagenesis following peer review. The version of record Alotaibi, Amal AA and Najafzadeh, Mojgan and Davies, Justin D and Baumgartner, Adi and Anderson, Diana (2017) Inhibition of survivin expression after using oxaliplatin and vinflunine to induce cytogenetic damage in vitro in lymphocytes from colon cancer patients and healthy individuals. is available online at: https://academic.oup.com/mutage/article-abstract/doi/10.1093/mutage/gex022/4344798/
Status: Published
DOI: 10.1093/mutage/gex022
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica
School/Department: School of Health Sciences
URI: http://ray.yorksj.ac.uk/id/eprint/2365

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