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Multidrug-resistant Cancer Cells Facilitate E1-independent Adenoviral Replication

Impact for Cancer Gene Therapy

¹Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum Rechts der Isar, München, Germany; ²Institut für Pathologie and ³Institut für Immunologie, Universitätsklinikum Charité, Humboldt-Universität Berlin, Berlin, Germany; ⁴Max-Delbrück Centrum für Molekulare Medizin, Berlin, Germany; ⁵Institut für Transplantationsdiagnostik und Zelltherapeutika and ⁶Institut für Humangenetik und Anthropologie, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany; ⁷Department of Biochemistry, McMaster University, London, Ontario, Canada; and ⁸Center of Advanced European Studies and Research (CAESAR), Bonn, Germany

Resistance to chemotherapy is responsible for a failure of current treatment regimens in cancer patients. We have reported previously that the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug resistant-tumor phenotype. YB-1 predicts drug resistance and patient outcome in breast cancer. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In drug-resistant cancer cells and in adenovirus-infected cells YB-1 is found in the nucleus. Nuclear accumulation of YB-1 in adenovirus-infected cells is a function of the E1 region, and we have shown that YB-1 facilitates adenovirus replication. Here we report that E1A-deleted or mutant adenovirus vectors, such as Ad312 and Ad520, replicate efficiently in multidrug-resistant (MDR) cancer cells and induce an adenovirus cytopathic effect resulting in host cell lysis. Thus, replication-defective adenoviruses are a previously unrecognized vector system for a selective elimination of MDR cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors for the treatment of MDR malignant diseases in the clinical setting.

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