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Induction of Apoptosis by Bexarotene in Cutaneous T-Cell Lymphoma Cells

Relevance to Mechanism of Therapeutic Action¹

Departments of Dermatology [C. Z., P. H., X. N., M. D.] and Hematology [D. A. W.], The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

Purpose: Bexarotene is the first synthetic rexinoid approved for the treatment of all stages of cutaneous T-cell lymphoma (CTCL) however the mechanism of bexarotene action is unknown. We examined the effects of bexarotene on induction of apoptosis and expression of its cognate receptors in well-established CTCL cell lines (MJ, Hut78, and HH).

Experimental Design: CTCL cells were treated with 0.1, 1, and 10 µM bexarotene for 24, 48, 72, and 96 h. Apoptosis was determined by flow-cytometry analysis of sub-G₁ hypodiploid nuclei and annexin V binding populations. Apoptosis-associated proteins and retinoid receptors were detected by Western blots.

Results: Bexarotene treatment at 1 and 10 µM for 96 h increased the number of cells with sub-G₁ populations and annexin V binding in a dose-dependent manner compared with vehicle controls (DMSO) in all three cell lines, respectively. Bexarotene treatment suppressed the expression of retinoid X receptor and retinoic acid receptor proteins in all three lines compared with untreated controls. Bexarotene treatment decreased the protein levels of survivin, activated caspase-3, and cleaved poly(ADP-Ribose) polymerase, but had no obvious effect on expression of Fas/Fas ligand and bcl-2 proteins in all three CTCL lines.

Conclusions: Bexarotene treatment at clinically relevant concentrations causes apoptosis of CTCL cell lines in association with activation of caspase-3 and cleavage of poly(ADP-Ribose) polymerase, as well as down-regulation of retinoid X receptor , retinoic acid receptor , and survivin. These findings support apoptosis as a mechanism for bexarotene therapy in CTCL.

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