RETINOID-MEDIATED INHIBITION OF CELL-GROWTH WITH STIMULATION OF APOPTOSIS IN AGGRESSIVE B-CELL LYMPHOMAS

Retinoids have been shown to modulate cell growth and differentiation in a variety of human tumor cell types, but their effects on B-cell no n-Hodgkin's lymphomas (NHL-B) have not been explored, In this study, a ll-trans retinoic acid (ATRA) in the free form and liposome-encapsulat ed form (L-ATRA) were used to determine effects on fresh NHL-B patient cells as well as cell lines recently established from both HIV-negati ve and -positive NHL-B patient biopsies, Both ATRA and L-ATRA were fou nd to inhibit cell proliferation in NHL-B cells, However, L-ATRA was f ound to be superior to free ATRA in inhibiting cell proliferation of N HL-B cells and resulted in greater than 90% cell growth inhibition in a dose-dependent manner. In addition, L-ATRA also induced high levels of apoptosis in NHL-B cells in vitro, To delineate the apoptotic pathw ays involved, the expression of the apoptosis suppressor oncogene bcl- 2 was evaluated in different NHL-B cells with and without the t(14;18) chromosomal translocation, After L-ATRA exposure, more than a 50% red uction in the expression of bcl-2 protein was observed, bcl-2 message levels were also down-regulated in the L-ATRA-sensitive NHL-B cells, B ar protein levels were analyzed and found to be upregulated in L-ATRA- sensitive NHL-B cells, Similar results were observed in sensitive AIDS /lymphoma cell lines, Experiments using an RAR-alpha antagonist (RO 41 -5253) showed that both the proliferation inhibition and apoptosis ind uced by L-ATRA could be blocked in NHL-B cells. The findings of the pr esent study indicate that L-ATRA may possess therapeutic potential in blocking cell proliferation, inducing apoptosis, and regulating bcl-2 and bar expression in NHL-B and AIDS/lymphoma cells directly or indire ctly.