ABSTRACTS – ORAL PRESENTATIONS - AMCA, spol. s r.o.

P7. MOLECULAR MECHANISMS RESPONSIBLE FOR DIFFERENT MODULATION OF
THE CELL CYCLE PROGRESSION IN COLON CANCER CELLS TREATED WITH LA-12 AND
OXALIPLATIN
Iva Jelinkova 1,2 , Olga Vondalova Blanarova 1,2 , Jarmila Laukova 1,2 , Jirina Hofmanova 1,2 ,
Petr Sova 3 , Alois Kozubik 1,2 , Alena Hyrslova Vaculova 1
1
Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech
Republic, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic,
2
Institute of Experimental Biology, Faculty of Science, Masaryk University, Terezy
Novakove 64, 621 00 Brno, Czech Republic,
3
Platinum Pharmaceuticals a.s., Brno, Czech Republic
ivina@ibp.cz, vaculova@ibp.cz
Platinum-based antitumor agents such as oxaliplatin are used in the therapy of many
solid cancers including colorectum, but their use is limited by serious side effects and
intrinsic or acquired resistance. Therefore, an intensive search for novel more suitable
candidates is still ongoing. Recently, platinum (IV) adamantylamine ligand-containing
complex LA-12 has been introduced and shown as highly effective in many cancer cells
including cisplatin resistant. Platinum-based drugs express their cytotoxicity by creating
adducts on DNA that may result in initiation of DNA damage pathways. Activation of
these pathways leads to halting the progression of the cell cycle, providing the time
for DNA repair or induction of cell death. The key downstream target of DNA damage
signaling pathways is p53 protein, which is essential for the cell cycle arrest, apoptosis
and DNA repair. As a transcriptional target of p53, p21 protein is an important regulator
of cyclins and cyclin dependent kinases.
In our study, we compared the ability of oxaliplatin and LA-12 to modulate cell cycle and
induce cell death in colon carcinoma cell lines HCT116 and RKO, and investigated the
molecular mechanisms responsible for the differences in their response. We observed
that LA-12 exerted cytotoxicity independently on p53 and p21 status, and in significantly
lower concentration than oxaliplatin. Using p53/p21 deficient HCT116 cells, we also
confirmed the indispensable role of these regulators in oxaliplatin-induced G2 arrest
that was accompanied by downregulation of cyclin B1 and active Cdk1 (Flow cytometry,
western blotting). On the other hand, LA-12-induced toxicity was not associated with
p53- and p21-dependent G2-phase arrest and block in M phase entry observed in
oxaliplatin-treated cells. The higher cytotoxicity together with its ability to bypass the
cell cycle arrest important for the cellular damage repair suggest LA-12 as more effective
candidate for elimination of colon tumors with various genetic backgrounds when
compared to oxaliplatin.
This work was supported by IGA Ministry of Health of the Czech Republic NT 11201-
5, Czech Science Foundation P301/11/1730 and European Regional Development Fund
(CZ.1.07/2.3.00/20.0180).
Analytical Cytometry VII 95