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

VONDÁLOVÁ BLANÁŘOVÁ, Olga, Iva JELÍNKOVÁ, Alena HYRŠLOVÁ VACULOVÁ, P. SOVA, Jiřina HOFMANOVÁ and Alois KOZUBÍK. 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. Cell Proliferation. 2013, vol. 46, No 6, p. 665-676. ISSN 0960-7722. Available from: https://dx.doi.org/10.1111/cpr.12061.

Basic information

• Original name: 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
• Authors: VONDÁLOVÁ BLANÁŘOVÁ, Olga (203 Czech Republic, belonging to the institution), Iva JELÍNKOVÁ (203 Czech Republic, belonging to the institution), Alena HYRŠLOVÁ VACULOVÁ (203 Czech Republic), P. SOVA (203 Czech Republic), Jiřina HOFMANOVÁ (203 Czech Republic, belonging to the institution) and Alois KOZUBÍK (203 Czech Republic, belonging to the institution).
• Edition: Cell Proliferation, 2013, 0960-7722.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: Genetics and molecular biology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 3.280
• RIV identification code: RIV/00216224:14310/13:00082130
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1111/cpr.12061
• UT WoS: 000326233800007
• Keywords in English: COLORECTAL-CANCER; DNA-DAMAGE; MITOTIC CATASTROPHE; INDUCED APOPTOSIS; CYCLE ARREST; IN-VITRO; P53; CISPLATIN; ADAMANTYLAMINE; RESISTANCE
• Tags: AKR, rivok

Abstract

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.

Links

• MSM0021622430, plan (intention): Name: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies