PPARgamma-independent antitumor effects of thiazolidinediones.
The thiazolidinedione (TZD) family of PPARgamma agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer cells. Mounting evidence indicates that TZDs interfere with multiple signaling mechanisms independently of PPARgamma activation, which affect many aspects of cellular functions governing cell cycle progression and survival of cancer cells. Here, we review the "off-target" mechanisms that underlie the antitumor effects of TZDs with emphasis on three key pathways, namely, inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression of androgen receptor (AR) through Sp1 degradation. Relative to tumor cells, nonmalignant cells are resistant to these PPARgamma-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARgamma agonist activity provides a rationale for using TZDs as scaffolds for lead optimization to develop a novel class of antitumor agents with a unique mode of mechanism.
Wei
Shuo
S
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Yang
Jian
J
Lee
Su-Lin
SL
Kulp
Samuel K
SK
Chen
Ching-Shih
CS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D047495:PPAR gamma / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D051020:bcl-X Protein; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone; C039671:ciglitazone
Mol Pharmacol. 2006 May;69(5):1564-70
16452400
BMC Physiol. 2005 Feb 06;5(1):3
15694007
J Biol Chem. 2001 Oct 12;276(41):37731-4
11459852
Mol Pharmacol. 2005 Apr;67(4):1342-8
15653552
Cancer Res. 2005 Feb 15;65(4):1561-9
15735046
J Med Chem. 2008 Apr 10;51(7):2100-7
18335975
Mol Cell Biol. 2001 May;21(9):3057-70
11287611
Curr Opin Cell Biol. 2004 Dec;16(6):623-8
15530772
J Clin Invest. 2000 Aug;106(4):467-72
10953021
Cancer Res. 2000 Oct 1;60(19):5494-8
11034093
Cancer Res. 2007 Apr 1;67(7):3229-38
17409431
Clin Cancer Res. 2003 Jan;9(1):1-9
12538445
Biochem Biophys Res Commun. 2001 Sep 7;286(5):916-22
11527386
Cancer Res. 2003 Mar 1;63(5):958-64
12615709
J Biol Chem. 2004 Aug 20;279(34):35583-94
15190077
Nat Rev Mol Cell Biol. 2004 Sep;5(9):739-51
15340381
Cancer Res. 2003 Sep 15;63(18):5926-39
14522919
J Biol Chem. 2004 Oct 22;279(43):45020-7
15308623
Nat Rev Cancer. 2006 May;6(5):369-81
16633365
Eur J Cancer. 2005 Nov;41(16):2438-48
16209919
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3951-6
10097144
J Biol Chem. 2008 Sep 26;283(39):26759-70
18650423
J Biol Chem. 2002 Jun 21;277(25):22320-9
11940602
Mol Cancer Ther. 2002 Mar;1(5):357-63
12489852
J Biol Chem. 2001 Aug 10;276(32):29681-7
11397807
Mol Pharmacol. 2007 Sep;72(3):725-33
17569795
Diabet Med. 1999 Mar;16(3):179-92
10227562
Biochem J. 2003 Dec 15;376(Pt 3):607-13
12954078
Lancet Oncol. 2004 Jul;5(7):419-29
15231248
Mol Pharmacol. 2003 Feb;63(2):401-8
12527812
Eur J Pharmacol. 2000 Nov 3;407(3):227-35
11068018
Semin Cell Dev Biol. 2005 Jun;16(3):323-33
15840441
J Cell Biochem. 2004 Feb 15;91(3):513-27
14755682
Toxicol Sci. 2007 May;97(1):1-3
17575588
Hepatology. 2003 May;37(5):1086-96
12717389
Toxicol Lett. 2003 Mar 20;139(1):67-75
12595159
J Clin Endocrinol Metab. 2007 Feb;92(2):386-95
17148564
Apoptosis. 2006 Sep;11(9):1503-12
16820965
Cancer Res. 2001 Aug 15;61(16):6213-8
11507074
Endocr Relat Cancer. 2006 Jun;13(2):401-13
16728570
J Med Chem. 2006 Jul 27;49(15):4684-9
16854074