title: Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus.
abstract: Malignant melanoma is a highly aggressive cancer that retains functional p53 and p73, and drug unresponsiveness largely depends on defects in death pathways after epigenetic gene silencing in conjunction with an imbalanced p73/DNp73 ratio. We constructed oncolytic viruses armed with an inhibitor of deacetylation and/or p73 to specifically target metastatic cancer. Arming of the viruses is aimed at lifting epigenetic blockage and re-opening apoptotic programs in a staggered manner enabling both, efficient virus replication and balanced destruction of target cells through apoptosis. Our results showed that cooperative expression of shHDAC1 and p73 efficiently enhances apoptosis induction and autophagy of infected cells which reinforces progeny production. In vitro analyses revealed 100% cytotoxicity after infecting cells with OV.shHDAC1.p73 at a lower virus dose compared to control viruses. Intriguingly, OV.shHDAC1.p73 acts as a potent inhibitor of highly metastatic xenograft tumors in vivo. Tumor expansion was significantly reduced after intratumoral injection of 3 x 10⁸ PFU of either OV.shHDAC1 or OV.p73 and, most important, complete regression could be achieved in 100 % of tumors treated with OV.shHDAC1.p73. Our results point out that the combination of high replication capacity and simultaneous restoration of cell death routes significantly enhance antitumor activity.
authors: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany; These authors contributed equally to the work.
authors: Holger
authors: H
authors: Schipper
authors: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany; These authors contributed equally to the work.
authors: Vijay
authors: V
authors: Alla
authors: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors: Claudia
authors: C
authors: Meier
authors: Helmholtz University Group Oncolytic Adenoviruses, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Dirk M
authors: DM
authors: Nettelbeck
authors: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors: Ottmar
authors: O
authors: Herchenröder
authors: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.
authors: Brigitte M
authors: BM
authors: Pützer
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D019076:Transgenes; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1