Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma Journal Article
| Authors: | Adusumilli, P. S.; Chan, M. K.; Yun, S. C.; Hezel, M.; Chou, T. C.; Rusch, V. W.; Fong, Y. |
| Article Title: | Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma |
| Abstract: | Background: NV1066, a replication-competent oncolytic herpes simplex virus type 1 (HSV-1) attenuated by a deletion in the gene γ134.5, preferentially replicates in and kills malignant cells. γ134.5 encodes ICP34.5, a viral protein essential for productive replication, which has homology with mammalian stress response induced GADD34 (growth arrest and DNA damage-inducible protein). We hypothesized that cisplatin upregulates GADD34 expression, which enhances NV1066 replication and oncolysis. Methods: Ten human malignant pleural mesothelioma (MPM) cell lines were infected with NV1066 at multiplicities of infection (MOI; ratio of viral particles per tumor cell) 0.005 to 0.8 in vitro, with and without cisplatin (1 to 4 μM). In the MPM cell line VAMT, viral replication was determined by plaque assay, cell kill by lactate dehydrogenase assay, and GADD34 induction by quantitative RT-PCR and Western blot. Synergistic efficacy was confirmed by the isobologram and combination index methods of Chou-Talalay. GADD34 upregulation by cisplatin was inhibited with GADD34 siRNA to further confirm the synergistic efficacy dependence with GADD34. Results: Combination therapy with NV1066 and cisplatin showed strong synergism in epithelioid (H-2452, H-Meso), sarcomatoid (H-2373, H-28), and biphasic (JMN, Meso-9, MSTO-211H) MPM cell lines, and an additive effect in others. In VAMT cells combination therapy enhanced viral replication 4 to11-fold (p < 0.01) and cell kill 2 to 3-fold (p < 0.01). Significant dose reductions for both agents (2 to 600-fold) were achieved over a wide range of therapeutic-effect levels (LD50-LD99) without compromising cell kill. Synergistic cytotoxicity correlated with GADD34 upregulation (2 to 4-fold, p < 0.01) and was eliminated following transfection with GADD34 siRNA. Conclusion: Cisplatin-induced GADD34 expression selectively enhanced the cytotoxicity of the γ134.5-deficient oncolytic virus, NV1066. This provides a cellular basis for combination therapy with cisplatin and NV1066 to treat MPM and achieve synergistic efficacy, while minimizing dosage and toxicity. ©2005 Landes Bioscience. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; gene deletion; cisplatin; drug dose reduction; drug efficacy; drug potentiation; combined modality therapy; chemotherapy; antineoplastic agent; cell cycle proteins; reverse transcription polymerase chain reaction; infection; protein; small interfering rna; rna, small interfering; cytotoxicity; correlation analysis; statistical significance; genetic transfection; western blotting; gene therapy; oncolytic virus; oncolytic virotherapy; pleura mesothelioma; mesothelioma; malignant neoplastic disease; lactate dehydrogenase; herpesvirus 1, human; upregulation; virus replication; up-regulation; combination therapy; herpes simplex virus 1; virus particle; pleural neoplasms; enzyme assay; cell killing; antigens, differentiation; viral proteins; nv 1066; viral gene therapy; virus culture; hsv; growth arrest and dna damage inducible protein; virus oncolysate |
| Journal Title: | Cancer Biology and Therapy |
| Volume: | 5 |
| Issue: | 1 |
| ISSN: | 1538-4047 |
| Publisher: | Taylor & Francis Group |
| Date Published: | 2006-01-01 |
| Start Page: | 48 |
| End Page: | 53 |
| Language: | English |
| PUBMED: | 16294031 |
| PROVIDER: | scopus |
| PMCID: | PMC1383726 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 4 June 2012" - "Source: Scopus" |
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