title: The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells.
abstract: Selected HIV drugs, either of the protease inhibitor type or the nucleoside antagonist type, have been shown to exert tumoricidal effects. Here, we show that the HIV reverse transcriptase inhibitor Truvada, a combination drug of the cytidine analogue emtricitabine and the adenosine analogue tenofovir, induces DNA damage and cell cycle arrest in human cancer cells. Phosphorylation of the DNA repair enzyme H2AX by emtricitabine/tenofovir indicated that it interfered with the integrity of the DNA and replication machinery in human cancer cells. Long term incubation of cancer cells with emtricitabine/tenofovir caused the formation of multi-nuclear giant cells, further indicating DNA replication problems. When tested as single agents, the anti-tumoral activity of emtricitabine/tenofovir was predominantly caused by tenofovir, although the combination with emtricitabine enhanced its effect on cancer cells. Combined with established anti-cancer drugs, emtricitabine/tenofovir was preferentially found to enhance the cytotoxic effect of doxorubicin, a promising drug for the treatment of relapsed, chemoresistant cancer. These results show that especially the adenosine analogue tenofovir could be used to interfere with the proliferation machinery of human cancer cells and to be applied for chemosensitization of cancer cells to already established DNA-interacting drugs.
authors.affiliation: Department of Obstetrics and Gynecology, Campus Innenstadt, Ludwig-Maximilians-University Munich, Maistrasse 11, 80337 Munich, Germany. ansgar.bruening@med.uni-muenchen.de
authors.forename: Ansgar
authors.initials: A
authors.lastname: Brüning
authors.forename: Petra
authors.initials: P
authors.lastname: Burger
authors.forename: Andrea
authors.initials: A
authors.lastname: Gingelmaier
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mylonas
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D000068679:Emtricitabine; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D063065:Organophosphonates / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000473:pathology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir; D013997:Time Factors
chemical_list: D054697:Cytostatic Agents; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; C468783:H2AX protein, human; D006657:Histones; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D004317:Doxorubicin; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine; D000225:Adenine