Novel three-pronged strategy to enhance cancer cell killing in glioblastoma cell lines: histone deacetylase inhibitor, chemotherapy, and oncolytic adenovirus dl520.
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.
Bieler
Alexa
A
Institute of Experimental Oncology, Technical University of Munich, Klinikum Rechts-der-Isar, 81675 Munich, Germany.
Mantwill
Klaus
K
Dravits
Tanja
T
Bernshausen
Alexandra
A
Glockzin
Gabriel
G
Köhler-Vargas
Nadia
N
Lage
Hermann
H
Gansbacher
Bernd
B
Holm
Per S
PS
D000256:Adenoviridae / Q000187:drug effects / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015139:Blotting, Southern / Q000379:methods; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D015870:Gene Expression; D005840:Gentian Violet; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry / Q000379:methods; D000077146:Irinotecan; D050504:Oncolytic Viruses / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011991:Receptors, Virus / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011500:Protein Synthesis Inhibitors; D011991:Receptors, Virus; C012589:trichostatin A; D000077146:Irinotecan; D005840:Gentian Violet; D002166:Camptothecin