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 non-Hodgkin's lymphomas (NHL-B) have not been explored. In this study, all-trans retinoic acid (ATRA) in the free form and liposome-encapsulated form (L-ATRA) were used to determine effects on fresh NHL-B patient cells as well as cell lines recently established from both HIV-negative and -positive NHL-B patient biopsies. Both ATRA and L-ATRA were found to inhibit cell proliferation in NHL-B cells. However, L-ATRA was found to be superior to free ATRA in inhibiting cell proliferation of NHL-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 pathways 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% reduction 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. Bax protein levels were analyzed and found to be up-regulated 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 induced by L-ATRA could be blocked in NHL-B cells. The findings of the present study indicate that L-ATRA may possess therapeutic potential in blocking cell proliferation, inducing apoptosis, and
Sundaresan
A
A
Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Claypool
K
K
Mehta
K
K
Lopez-Berestein
G
G
Cabanillas
F
F
Ford
R J
RJ
D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D004304:Dosage Forms; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D016483:Lymphoma, AIDS-Related / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology* / Q000648:ultrastructure; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000008:administration & dosage* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D001565:Benzoates; D002839:Chromans; D004304:Dosage Forms; D008081:Liposomes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D051028:bcl-2-Associated X Protein; C084904:Ro 41-5253; D014212:Tretinoin