OBJECTIVES: Therapeutic 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 METHODS: Cell 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. RESULTS: Our 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 G2 -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. CONCLUSIONS: Higher 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.

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic v v i Brno 61265 Czech Republic; Department of Animal Physiology and Immunology Faculty of Science Institute of Experimental Biology Masaryk University Brno 621 00 Czech Republic

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Kelland L (2007) The resurgence of platinum‐based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584. PubMed

Bastos DA, Ribeiro SC, De Freitas D, Hoff PM (2010) Combination therapy in high‐risk stage II or stage III colon cancer: current practice and future prospects. Ther. Adv. Med. Oncol. 2, 261–272. PubMed PMC

Douillard J‐Y, Bennouna J, Senellart H (2008) Is XELOX equivalent to FOLFOX or other continuous‐infusion 5‐fluorouracil chemotherapy in metastatic colorectal cancer? Clin. Colorectal Cancer 7, 206–211. PubMed

Choy H, Park C, Yao M (2008) Current status and future prospects for satraplatin, an oral platinum analogue. Clin. Cancer Res. 14, 1633–1638. PubMed

Zák F, Turánek J, Kroutil A, Sova P, Mistr A, Poulová A PubMed

Kozubík A, Horváth V, Svihálková‐Sindlerová L, Soucek K, Hofmanová J, Sova P PubMed

Horváth V, Blanárová O, Svihálková‐Sindlerová L, Soucek K, Hofmanová J, Sova P PubMed

Svihálková‐Sindlerová L, Foltinová V, Vaculová A, Horváth V, Soucek K, Sova P PubMed

Sova P, Mistr A, Kroutil A, Zak F, Pouckova P, Zadinova M (2005) Preclinical anti‐tumor activity of a new oral platinum(IV) drug LA‐12. Anticancer Drugs 16, 653–657. PubMed

Sova P, Mistr A, Kroutil A, Zak F, Pouckova P, Zadinova M (2006) Comparative anti‐tumor efficacy of two orally administered platinum(IV) drugs in nude mice bearing human tumor xenografts. Anticancer Drugs 17, 201–206. PubMed

Sova P, Chladek J, Zak F, Mistr A, Kroutil A, Semerad M PubMed

Sova P, Mistr A, Kroutil A, Semerád M, Chlubnová H, Hrusková V PubMed

Kaspárková J, Nováková O, Vrána O, Intini F, Natile G, Brabec V (2006) Molecular aspects of antitumor effects of a new platinum(IV) drug. Mol. Pharmacol. 70, 1708–1719. PubMed

Kvardova V, Hrstka R, Walerych D, Muller P, Matoulkova E, Hruskova V PubMed PMC

Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265–7279. PubMed

Niida H, Nakanishi M (2006) DNA damage checkpoints in mammals. Mutagenesis 21, 3–9. PubMed

Yu J, Zhang L (2005) The transcriptional targets of p53 in apoptosis control. Biochem. Biophys. Res. Commun. 331, 851–858. PubMed

Green DR, Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127–1130. PubMed PMC

Murray‐Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nat. Rev. Mol. Cell Biol. 9, 702–712. PubMed

Broude EV, Swift ME, Vivo C, Chang B‐D, Davis BM, Kalurupalle S PubMed

Coqueret O (2003) New roles for p21 and p27 cell‐cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 13, 65–70. PubMed

Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP PubMed

Innocente SA, Lee JM (2005) p53 is a NF‐Y‐ and p21‐independent, Sp1‐dependent repressor of cyclin B1 transcription. FEBS Lett. 579, 1001–1007. PubMed

Basile V, Mantovani R, Imbriano C (2006) DNA damage promotes histone deacetylase 4 nuclear localization and repression of G2/M promoters, via p53 C‐terminal lysines. J. Biol. Chem. 281, 2347–2357. PubMed

Müller GA, Engeland K (2010) The central role of CDE/CHR promoter elements in the regulation of cell cycle‐dependent gene transcription. FEBS J. 277, 877–893. PubMed

Waldman T, Kinzler KW, Vogelstein B (1995) p21 is necessary for the p53‐mediated G1 arrest in human cancer cells. Cancer Res. 55, 5187–5190. PubMed

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real‐time quantitative PCR and the 2(‐Delta Delta C(T)) Method. Methods 25, 402–408. PubMed

Juan G, Traganos F, Darzynkiewicz Z (1999) Histone H3 phosphorylation in human monocytes and during HL‐60 cell differentiation. Exp. Cell Res. 246, 212–220. PubMed

Misset JL, Bleiberg H, Sutherland W, Bekradda M, Cvitkovic E (2000) Oxaliplatin clinical activity: a review. Crit. Rev. Oncol. Hematol. 35, 75–93. PubMed

Liu YP, Ling Y, Qi QF, Zhang YP, Zhang CS, Zhu CT PubMed PMC

McWhinney SR, Goldberg RM, McLeod HL (2009) Platinum neurotoxicity pharmacogenetics. Mol. Cancer Ther. 8, 10–16. PubMed PMC

Hata T, Yamamoto H, Ngan CY, Koi M, Takagi A, Damdinsuren B PubMed

Arango D, Wilson AJ, Shi Q, Corner GA, Arañes MJ, Nicholas C PubMed PMC

Hayward RL, Macpherson JS, Cummings J, Monia BP, Smyth JF, Jodrell DI (2004) Enhanced oxaliplatin‐induced apoptosis following antisense Bcl‐xl down‐regulation is p53 and Bax dependent: genetic evidence for specificity of the antisense effect. Mol. Cancer Ther. 3, 169–178. PubMed

Chiu S‐J, Hsu T‐S, Chao J‐I (2006) Opposing securin and p53 protein expression in the oxaliplatin‐induced cytotoxicity of human colorectal cancer cells. Toxicol. Lett. 167, 122–130. PubMed

Rakitina TV, Vasilevskaya IA, O'Dwyer PJ (2007) Inhibition of G1/S transition potentiates oxaliplatin‐induced cell death in colon cancer cell lines. Biochem. Pharmacol. 73, 1715–1726. PubMed

Toscano F, Parmentier B, Fajoui ZE, Estornes Y, Chayvialle J‐A, Saurin J‐C PubMed

Zaanan A, Cuilliere‐Dartigues P, Guilloux A, Parc Y, Louvet C, De Gramont A PubMed

Hrstka R, Powell DJ, Kvardova V, Roubalova E, Bourougaa K, Candeias MM PubMed

Roubalová E, Kvardová V, Hrstka R, Borilová S, Michalová E, Dubská L PubMed

Kozubík A, Vaculová A, Soucek K, Vondrácek J, Turánek J, Hofmanová J (2008) Novel Anticancer Platinum(IV) Complexes with Adamantylamine: their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism. Met. Based Drugs 2008, 417897. PubMed PMC

Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM‐Chk2‐Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847. PubMed

Castedo M, Perfettini JL, Roumier T, Kroemer G (2002) Cyclin‐dependent kinase‐1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ. 9, 1287–1293. PubMed

Voland C, Bord A, Péleraux A, Pénarier G, Carrière D, Galiègue S PubMed

Chiu S‐J, Lee Y‐J, Hsu T‐S, Chen W‐S (2009) Oxaliplatin‐induced gamma‐H2AX activation via both p53‐dependent and ‐independent pathways but is not associated with cell cycle arrest in human colorectal cancer cells. Chem. Biol. Interact. 182, 173–182. PubMed

Fujie Y, Yamamoto H, Ngan CY, Takagi A, Hayashi T, Suzuki R PubMed

William‐Faltaos S, Rouillard D, Lechat P, Bastian G (2006) Cell cycle arrest and apoptosis induced by oxaliplatin (L‐OHP) on four human cancer cell lines. Anticancer Res. 26, 2093–2099. PubMed

Horváth V, Soucek K, Svihálková‐Sindlerová L, Vondrácek J, Blanárová O, Hofmanová J PubMed

Russell P, Nurse P (1986) cdc25 +  functions as an inducer in the mitotic control of fission yeast. Cell 45, 145–153. PubMed

Russell P, Nurse P (1987) Negative regulation of mitosis by wee1 + , a gene encoding a protein kinase homolog. Cell 49, 559–567. PubMed

Cisplatin or LA-12 enhance killing effects of TRAIL in prostate cancer cells through Bid-dependent stimulation of mitochondrial apoptotic pathway but not caspase-10

Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells

Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells