title: Reverse transcriptase inhibitors induce cell differentiation and enhance the immunogenic phenotype in human renal clear-cell carcinoma.
abstract: Reverse transcriptase (RT) inhibitors are emerging as a novel class of anticancer differentiating agents, active in several human tumor cell models, such as melanoma and prostate, thyroid and colon carcinoma. Indeed, much evidence suggests that they may act by inhibiting endogenous RT, a gene highly expressed in undifferentiated and transformed cells. We therefore evaluated whether endogenous RT may represent a new molecular target in the treatment of human renal clear-cell carcinoma, a neoplasm with very low sensitivity to standard pharmacological therapies. Efavirenz and nevirapine, 2 non-nucleosidic RT inhibitors commonly used in HIV patients, either induced a reversible downregulation of cell proliferation or enhanced cell differentiation in primary cultures of human renal carcinoma cells characterized by high levels of endogenous RT activity. Both agents upregulated the expression of the vitamin D receptor and calbindin 28k genes, which are constitutively expressed in renal tubular cells, and induced vitamin D signaling by enhancing the ability of tumor cells to upregulate the vitamin D-dependent gene, CYP24. Furthermore, efavirenz- and nevirapine-differentiated tumor cells exhibited an immunogenic phenotype with an increased expression of HLA-I and CD40 antigens and an enhanced ability to elicit a specific T-cell response in mixed lymphocyte/tumor-cell cultures. Indeed, renal carcinoma cells exposed to efavirenz induced a CD8(+)CCR7-CD45RA(-) effector memory T-cell phenotype, whereas untreated RCC cells induced a CD8(+)CCR7(+)CD45RA(-) central memory T-cell phenotype. These data suggest that RT inhibitors may be a novel tool in the treatment of human renal clear-cell carcinoma, potentially able to enhance the immunogenic potential of tumor cell.
authors: Clinical Oncology Unit, Department of Medical Sciences, University of Foggia, Foggia, Italy.
authors: Matteo
authors: M
authors: Landriscina
authors: Settimia Anna
authors: SA
authors: Altamura
authors: Leonarda
authors: L
authors: Roca
authors: Margherita
authors: M
authors: Gigante
authors: Annamaria
authors: A
authors: Piscazzi
authors: Elisabetta
authors: E
authors: Cavalcanti
authors: Eleonora
authors: E
authors: Costantino
authors: Carlo
authors: C
authors: Barone
authors: Mauro
authors: M
authors: Cignarelli
authors: Loreto
authors: L
authors: Gesualdo
authors: Elena
authors: E
authors: Ranieri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology*; D018613:Microscopy, Confocal; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D018894:Reverse Transcriptase Inhibitors