Higher anti-tumour efficacy of platinum(IV) complex LA-12 is associated with its ability to bypass M-phase entry block induced in oxaliplatin-treated human colon cancer cells

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Authors

VONDÁLOVÁ BLANÁŘOVÁ Olga JELÍNKOVÁ Iva HYRŠLOVÁ VACULOVÁ Alena SOVA P. HOFMANOVÁ Jiřina KOZUBÍK Alois

Year of publication 2013
Type Article in Periodical
Magazine / Source Cell Proliferation
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1111/cpr.12061
Field Genetics and molecular biology
Keywords COLORECTAL-CANCER; DNA-DAMAGE; MITOTIC CATASTROPHE; INDUCED APOPTOSIS; CYCLE ARREST; IN-VITRO; P53; CISPLATIN; ADAMANTYLAMINE; RESISTANCE
Description ObjectivesTherapeutic potential of conventionally used platinum-based drugs in treatment of colorectal tumours has been limited due to high incidence of tumour resistance to them and to their severe side effects. This evokes a search for more suitable anti-cancer drugs. We have compared ability of oxaliplatin and a novel platinum(IV) complex, LA-12, to modulate the cell cycle and induce apoptosis in human colon adenocarcinoma HCT116 wt and p53/p21 null cells, and have investigated molecular mechanisms involved. Materials and methodsCell cycle-related changes were analysed by flow cytometry (bromodeoxyuridine/propidium iodide staining, histone H3 phosphorylation). Apoptosis was detected using flow cytometry (assays monitoring caspase activity) and fluorescence microscopy (nuclear morphology). Changes in levels of genes/proteins involved in cell cycle and apoptosis regulation were examined by RT-PCR and western blotting. ResultsOur results highlight the outstanding ability of LA-12 to induce effective elimination of colon cancer cells independently of p53/p21, and in significantly lower doses compared to oxaliplatin. While oxaliplatin induced p53- and p21-dependent G(2)-phase arrest associated with downregulation of cyclin B1 and Cdk1, LA-12 allowed cells to enter M-phase of the cell cycle regardless of p53/p21 status. ConclusionsHigher malignant cell toxicity and ability to bypass cell cycle arrest important for the cell damage repair suggest LA-12 to be a more effective candidate for elimination of colon tumours from a variety of genetic backgrounds, compared with oxaliplatin.
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