adenovirus-mediated sensitization to the cytotoxic drugs docetaxel and mitoxantrone is dependent on regulatory domains in the e1acr1 gene-regionadenovirus-mediated敏感的细胞毒性药物紫杉醇和米托蒽醌是e1acr1依赖监管领域基因区域.pdfVIP

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adenovirus-mediated sensitization to the cytotoxic drugs docetaxel and mitoxantrone is dependent on regulatory domains in the e1acr1 gene-regionadenovirus-mediated敏感的细胞毒性药物紫杉醇和米托蒽醌是e1acr1依赖监管领域基因区域.pdf

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adenovirus-mediated sensitization to the cytotoxic drugs docetaxel and mitoxantrone is dependent on regulatory domains in the e1acr1 gene-regionadenovirus-mediated敏感的细胞毒性药物紫杉醇和米托蒽醌是e1acr1依赖监管领域基因区域

Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region ¤a ¨ ¤b Enrique Miranda , Hector Maya Pineda, Daniel Oberg , Gioia Cherubini, Zita Garate, Nick R. Lemoine, ´ Gunnel Hallden* Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom Abstract Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdDD and dl922–947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1ADCR2 mutants (AdE1A1108, dl922–947) and