The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sézary syndrome cells.
The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) can serve as a ligand for the peroxisome proliferator activator receptor-gamma (PPAR-gamma) and has been shown to inhibit cell proliferation, and to induce differentiation and apoptosis in tumor cell lines. Bexarotene is an RXR-selective retinoid that can induce apoptosis of mycosis fungoides (MF) and Sézary syndrome (SS) cells. Since the PPAR-gamma and RXR receptors can form heterodimers, we studied the effects of CDDO and its synergism with bexarotene on apoptosis in MF/SS cell lines (MJ, Hut78, and HH) and freshly isolated peripheral blood lymphocytes (PBL) from SS patients with circulating atypical T cells (CD4+CD26-). CDDO treatment at 1-5 microM for 48 h caused a concentration-dependent apoptosis in three MF/SS cell lines and patients' PBL compared to vehicle controls. Bexarotene augmented CDDO-induced apoptosis in these cells. PPAR-gamma was expressed but decreased by 47% in MJ, 42% in Hut78, and 77% in HH cells following CDDO treatment. The anti-apoptotic protein bcl-xL, but not bcl-2, was decreased by 69% in MJ, 31% in Hut78, and 59% in HH cells and caspase-3 was activated following CDDO treatment. Interestingly, the PPAR-gamma antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-gamma agonist rosiglitazone required much higher concentrations (>50 microM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-gamma and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-gamma-independent mechanism. Our findings suggest the rationale for further investigation of the clinical potential of CDDO, either alone or in combination with bexarotene for MF/SS patients.
Zhang
Chunlei
C
Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ni
Xiao
X
Konopleva
Marina
M
Andreeff
Michael
M
Duvic
Madeleine
M
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077610:Bexarotene; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D009182:Mycosis Fungoides; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D012751:Sezary Syndrome; D012878:Skin Neoplasms; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D016588:Anticarcinogenic Agents; D007155:Immunologic Factors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D009569:Nitric Oxide; D009828:Oleanolic Acid; D000077610:Bexarotene; D015230:Prostaglandin D2