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Communication Dans Un Congrès Année : 2012

New thiazolidinedione derivatives with PPARg-independent activity: high inhibition of breast cancer cell proliferation with low toxicity towards human hepatocytes

Résumé

Background: Breast cancer is the most frequent cancer in women. The development of de novo and acquired resistance to therapies and the absence of targeted therapy for some types of tumours are strong motivations for discovering new therapeutic agents. Thiazolidinediones (TZD) are studied in this context. These PPARg ligands have antiproliferative effects in vitro and in vivo and they were tested in clinical trials. Nevertheless compounds like troglitazone (TGZ) display hepatotoxicity. More recently, it was shown that in fact,TZD exert their anticancer effects mainly in a PPARg-independent manner. Therefore, we synthesized new TZD derivatives (D2 family) devoid of PPARg agonist activity. We studied their mechanism of action and their toxicity towards human hepatocytes before performing in vivo experiments on murine models. Material and Methods: TGZ derivatives were obtained by chemical synthesis. We used hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231)breast cancer cell lines as well as primary cultures of human hepatocytes. Proliferation and toxicity were studied with the Cell titer glo and MTT assays respectively. Gene expressions were studied by microarray, RT-PCR, western blotting and immunocytochemistry. RNA interference was used for gene silencing. Results: The PPARg-independent activity of D2-TZD in breast cancer cells was associated with a very early increase in intracellular calcium (after 2 minutes) followed by ERK1/2 activation (after 5 minutes) and a transient increase in the expression of the transcription factor "Early Growth Response gene 1" (maximum after 3 hours). Endoplasmic reticulum stress and proteasomal degradation of cyclin D1 and ERalpha occurred later. D2-TGZ and TGZ had similar antiproliferative efficiencies: their IC50 were 29.7 and 35.4 mM respectively in MCF7 cells and 16.6 and 15.8 mM in MDA-MB-231 cells. Among the new D2-TGZ derivatives that we obtained, some of them were more potent than TGZ and D2-TGZ with IC50 around 5 mM. Furthermore, these derivatives displayed a lower toxicity towards human hepatocytes than the parent compound TGZ (1.6-fold when used at 100 mM). Conclusions: Our work contributed to a better understanding of the PPARg-independent effects of TZD. We were able to obtain derivatives which were more potent to inhibit breast cancer cell proliferation and less toxic towards hepatocytes. This opens the possibility to start in vivo experiments in mouse models of breast cancer.

Domaines

Cancer

Dates et versions

hal-00747357 , version 1 (31-10-2012)

Identifiants

Citer

Christelle Colin, Sarra Chbicheb, Xiao Yao, Andrea Bordessa, Michel Boisbrun, et al.. New thiazolidinedione derivatives with PPARg-independent activity: high inhibition of breast cancer cell proliferation with low toxicity towards human hepatocytes. 22nd Biennial Congress of the European Association for Cancer Research, EACR-22, Jul 2012, Barcelone, Spain. pp.CDROM, ⟨10.1016/S0959-8049(12)71613-1⟩. ⟨hal-00747357⟩
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