Synergy between PPARgamma ligands and platinum-based drugs in cancer.
PPARgamma is a member of the nuclear receptor family for which agonist ligands have antigrowth effects. However, clinical studies using PPARgamma ligands as a monotherapy failed to show a beneficial effect. Here we have studied the effects of PPARgamma activation with chemotherapeutic agents in current use for specific cancers. We observed a striking synergy between rosiglitazone and platinum-based drugs in several different cancers both in vitro and using transplantable and chemically induced "spontaneous" tumor models. The effect appears to be due in part to PPARgamma-mediated downregulation of metallothioneins, proteins that have been shown to be involved in resistance to platinum-based therapy. These data strongly suggest combining PPARgamma agonists and platinum-based drugs for the treatment of certain human cancers.
Girnun
Geoffrey D
GD
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Naseri
Elnaz
E
Vafai
Scott B
SB
Qu
Lishu
L
Szwaya
Jeffrey D
JD
Bronson
Roderick
R
Alberta
John A
JA
Spiegelman
Bruce M
BM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004357:Drug Synergism; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016190:Carboplatin