Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes.
Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.
Pomponi
F
F
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Cariati
R
R
Zancai
P
P
De Paoli
P
P
Rizzo
S
S
Tedeschi
R M
RM
Pivetta
B
B
De Vita
S
S
Boiocchi
M
M
Dolcetti
R
R
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D001565:Benzoates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002472:Cell Transformation, Viral; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005050:Etretinate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D004854:Herpesvirus 4, Human; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D011990:Receptors, Transferrin; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000954:Antigens, Surface; D001565:Benzoates; C068126:CD71 antigen; D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D011990:Receptors, Transferrin; D012176:Retinoids; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014212:Tretinoin; D005050:Etretinate; C034814:ethyl-p-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl)benzoic acid; C081137:mofarotene; D015474:Isotretinoin