Combined low doses of PPARgamma and RXR ligands trigger an intrinsic apoptotic pathway in human breast cancer cells.
Ligand activation of peroxisome proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPARgamma ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor p53 and its effector p21(WAF1/Cip1). Functional experiments indicate that the nuclear factor-kappaB site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of p53 in PPARgamma/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPARgamma and RXR ligands may provide a therapeutic advantage in breast cancer treatment.
Bonofiglio
Daniela
D
Faculty of Pharmacy Nutritional and Health Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy.
Cione
Erika
E
Qi
Hongyan
H
Pingitore
Attilio
A
Perri
Mariarita
M
Catalano
Stefania
S
Vizza
Donatella
D
Panno
Maria Luisa
ML
Genchi
Giuseppe
G
Fuqua
Suzanne A W
SA
Andò
Sebastiano
S
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000166:cytology / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D047488:Retinoid X Receptors / Q000819:agonists; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014212:Tretinoin / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D000077154:Rosiglitazone; D000077556:Alitretinoin; D014212:Tretinoin