The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis.

BACKGROUND: Bexarotene (Targretin®) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. METHODS: With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. RESULTS: Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC50) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome. CONCLUSIONS: UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs.

Comparison of fetal and adult marrow stromal cells in osteogenesis with and without glucocorticoids.

To better understand the potential use of fetal marrow stromal cells (MSCs) in bone tissue engineering, we compared the ability of these cells with those of adult MSCs with respect to osteoblasts differentiation in the presence or absence of glucocorticoids. Cells were grown for 3-4 weeks in basal medium or supplemented with 100 nM dexamethasone (DEX, a synthetic glucocorticoid analog) or with 50 microM L-ascorbate and 10 mM glycerol-2-phosphate (AS+GP) or with AS+GP+DEX. At various time points in culture, the following parameters were compared between fetal and adult MSCs: cell morphology, cell proliferation, alkaline phosphatase activity, calcium (45Ca) uptake, von Kossa staining, and glucocorticoids receptor expression were analyzed. Compared with adult MSCs, fetal cells showed a less dramatic change to cuboidal morphology in DEX-containing media. Fetal MSCs in all media conditions showed higher proliferation rates and lower alkaline phosphatase activities (p < 0.001) than adult cells. Both fetal and adult MSCs responded similarly in DEX-containing media with respect to suppressing cell proliferation, stimulating alkaline phosphatase activity, and consistently accumulating calcium (usually higher in fetal cells) with subsequent formation of mineralized matrix when compared with cells cultured in AS+GP. Our findings further implicate the requirement of glucocorticoids in osteogenesis. In conclusion, compared with adult MSCs, fetal cells showed greater ability in sustaining cell proliferation and calcium uptake suggesting that they may be useful for bone tissue repair.