Oxaliplatin with PPARγ ligand modulate regulation of the cell cycle and cell death of colon tumors

 Platinum chemotherapeutics are commonly used in the treatment of many solid tumors, as for example testicular, bladder, ovarian, colorectal, lung, head and neck cancers etc. Oxaliplatin (L-OHP) in combination with fluoropyrimidines, leucovorin or irinotecan (scheme FOLFOX, FOLFIRI etc.) is widely used in chemotherapy treatment of colon tumors. Dose-limiting toxicities and resistance are significant problem in successful treatment of patients. Usually, more than one resistance mechanism is activated. Therefore, new combined chemotherapies are considered. We focused on effect of combination of L-OHP with PPAR gama ligand (rosiglitazone; RGZ ) in human colon cancer cell lines.

 PPAR alfa beta/delta gama (Peroxisome Proliferator – Activated Receptors) belong to large family of nuclear receptors. They could influent regulation of glucose and lipid metabolism, energy balance, adipocyte differentiation, atherosclerosis, diabetes, inflammation and cancer. However, the effect of PPARγ in colorectal tumors remains still controversial. PPARγ has been described in both normal and many different cancer cell types. In colorectal tumor patients with higher PPARγ expression the improved survival was observed.

 Our results have shown that RGZ increased activity of PPARγ receptor and decreased proliferation of colon cancer cells in dose – dependent manner. Western blot analysis and immunostaining have shown that RGZ decreased nuclear localization and expression of PPARγ. Interestingly, after 24 hours RGZ slightly increased BrdU (5-bromo-2-deoxyuridine) incorporation into the nucleus.

 Combination of RGZ with L-OHP decreased cell proliferation, arrested the cell cycle in G2/M, increased apoptosis, and increased cell cycle related and DNA damage protein expression. We suggest that increased percentage of active BrdU cells by RGZ may supports the effects of L-OHP.

 This work was supported by grant of Internal Grant Agency of Ministry of Health of the Czech Republic No. NT/11201– 5, grant Czech Science Foundation No. P301/11/1730 and FNUSA-ICRC European Regional Development Fund no. CZ.1.05/1.1.00/02.0123.