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- Title
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.
- Authors
Chunlei Zhang; Xiao Ni; Konopleva, Marina; Andreeff, Michael; Duvic, Madeleine
- Abstract
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-γ (PPAR-γ) 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-γ 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 μM 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-γ 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-γ antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-γ agonist rosiglitazone required much higher concentrations (>50 μM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-γ and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-γ-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.
- Publication
Journal of Investigative Dermatology, 2004, Vol 123, Issue 2, p380
- ISSN
0022-202X
- Publication type
Academic Journal
- DOI
10.1111/j.0022-202X.2004.23207.x