The effect of PPAR gamma ligands and platinum – based drugs on colorectal cancer cells with acquired resistance

PPARs (Peroxisome Proliferator - Activated Receptors) are ligand – activated transcription factors. PPAR family (PPAR alpha, PPAR beta/delta and PPAR gamma) was identified more than 20 years ago. Many studies have revealed that PPAR influences important biological functions, including inflammation, cell survival and differentiation. PPAR gamma agonists are already used for treatment of type II diabetes mellitus. However, in cancer cells PPAR gamma role as tumor suppressor or oncogene is still unclear. Overall survival of patients with colorectal cancer may be better in patients with higher PPAR gamma expression than in patients with lower expression in their primary tumors. Platinum - based drugs are extensively used for treating cancer but their application can be limited by toxic side effects and acquired resistance. Therefore, new approaches of combined chemotherapy are considered. Thus, our interest was focused on the common treatment of platinum drugs and PPAR gamma ligand in regulation of colon cell response.

We hypothesized, that the combined treatment might extend the use of PPAR gamma ligand (rosiglitazone) and platinum drugs (oxaliplatin, cisplatin and a new platinum (IV) complex LA-12) to cancer cells with acquired resistance.

We prepared resistant clones of colon cancer cell line HT-29 to oxaliplatin by cultivation with increasing concentration of this platinum drug for 3 months. The tests of cytotoxicity validated that clones are resistant to oxaliplatin. Moreover, flow cytometry analysis showed that treatment of oxaliplatin-resistant HT-29 cells by LA-12 significantly increased membrane lipid organization. PPAR gamma expression was increased by LA-12 with maximum after 5-8 hour treatment. This induced expression was blocked by siRNA. Further, we performed experiments where we compared effect of rosiglitazone and platinum drugs on protein expression of epithelial-to-mesenchymal transition (EMT). Expression of EMT proteins after platinum drug treatment with or without rosiglitazone pre-treatment was not changes in HCT-116 colon cancer cell line sensitive to platinum drugs. Rosiglitazone in combined treatment with platinum drugs decreased cell proliferation, arrested the cell cycle, increased apoptosis and changed membrane lipid structure in colon cancer cells without acquired resistance. Our results also demonstrated that rosiglitazone pretreatment increased sensitivity of colon cancer cells to platinum- based drugs.

This work was supported by grant of Internal Grant Agency of Ministry of Health of the Czech Republic No. NT/11201-5 and grant Czech Science Foundation No. P301/11/1730.