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1.
Cancer Res ; 66(14): 7195-202, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16849566

ABSTRACT

Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic Therapy.


Subject(s)
Adenoviridae/physiology , Antineoplastic Agents/pharmacology , DNA-Binding Proteins/metabolism , Genes, MDR/genetics , Multidrug Resistance-Associated Proteins/genetics , Oncolytic Virotherapy/methods , Prostatic Neoplasms/therapy , Adenoviridae/genetics , Adenovirus E2 Proteins/genetics , Animals , Cell Nucleus/metabolism , Combined Modality Therapy , Daunorubicin/pharmacology , Docetaxel , Down-Regulation , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , Male , Mice , Mice, Inbred BALB C , Multidrug Resistance-Associated Proteins/biosynthesis , Nuclear Proteins , Promoter Regions, Genetic , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/virology , Taxoids/pharmacology , Virus Replication , Xenograft Model Antitumor Assays , Y-Box-Binding Protein 1
2.
Hum Gene Ther ; 17(1): 55-70, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16409125

ABSTRACT

Resistance to radiation and chemotherapy remains an obstacle to the treatment of brain tumors. We have demonstrated that the replication-deficient adenovirus d1520, which lacks the E1A 13S protein, replicates efficiently and exhibits oncolytic potential in multidrug-resistant cells with nuclear localization of the human transcription factor YB-1. However, besides others, key factors regarding oncolytic virotherapy are limited tumor transduction rate and low replication efficiency. The objective of this study was to determine whether the chemotherapeutic agent irinotecan, by enhancing nuclear localization of YB-1, and the histone deacetylase inhibitor trichostatin A, by upregulating coxsackievirus-adenovirus receptor (CAR) expression, could augment replication of and cell lysis by adenovirus dl520 in glioblastomas in vitro. We found that trichostatin A upregulated CAR expression and that irinotecan caused increased nuclear localization of YB-1 in both glioblastoma cell lines. Irinotecan alone, and trichostatin A alone, enhanced replication of and cell lysis by dl520. Importantly, when combining both agents, the replication efficiency (maximum, 27-fold) and induction of cytopathic effect (maximum, 3.8-fold) of dl520 were further augmented significantly. These results support the hypothesis that the enhanced oncolytic effect of dl520, after incubation with chemotherapeutic agents, is mediated by an increased accumulation of YB-1 in the nucleus (due to irinotecan) and by upregulation of CAR (due to trichostatin A). Thus, therapy combining virotherapy, chemotherapy, and histone deacetylase inhibitor treatment is a novel approach to enhance the oncolytic efficacy of dl520.


Subject(s)
Brain Neoplasms/therapy , Enzyme Inhibitors/therapeutic use , Glioblastoma/therapy , Histone Deacetylase Inhibitors , Oncolytic Viruses/physiology , Adenoviridae/drug effects , Adenoviridae/physiology , Antineoplastic Agents, Phytogenic/pharmacology , Blotting, Southern/methods , Brain Neoplasms/pathology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/therapeutic use , Coxsackie and Adenovirus Receptor-Like Membrane Protein , Enzyme Inhibitors/pharmacology , Fibroblasts/cytology , Gene Deletion , Gene Expression , Gentian Violet , Glioblastoma/pathology , HeLa Cells , Humans , Hydroxamic Acids/pharmacology , Hydroxamic Acids/therapeutic use , Immunohistochemistry/methods , Irinotecan , Oncolytic Viruses/drug effects , Protein Synthesis Inhibitors/pharmacology , Receptors, Virus/analysis , Receptors, Virus/metabolism , Tumor Cells, Cultured
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