Survivin silencing and TRAIL expression using oncolytic adenovirus increase anti-tumorigenic activity in gemcitabine-resistant pancreatic cancer cells

Autor: Seungha Lee, Hye Jin Choi, Jae J. Song, Suyeon Je, Zhezhu Han, Chi Yong Eom, Joo Hang Kim
Rok vydání: 2015
Předmět:
0301 basic medicine
Oncology
Cancer Research
Survivin
Clinical Biochemistry
Pharmaceutical Science
Apoptosis
Deoxycytidine
Inhibitor of Apoptosis Proteins
TNF-Related Apoptosis-Inducing Ligand
Small hairpin RNA
Mice
0302 clinical medicine
Nude mouse
RNA
Small Interfering
Oncolytic Virotherapy
biology
Combined Modality Therapy
Oncolytic Viruses
030220 oncology & carcinogenesis
Female
RNA Interference
medicine.drug
Oncolytic adenovirus
Antimetabolites
Antineoplastic
medicine.medical_specialty
Down-Regulation
Mice
Nude
Adenoviridae
03 medical and health sciences
Cell Line
Tumor
Internal medicine
Pancreatic cancer
medicine
Animals
Humans
Gene silencing
neoplasms
Pharmacology
business.industry
Biochemistry (medical)
Cell Biology
biology.organism_classification
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Pancreatic Neoplasms
HEK293 Cells
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
business
Zdroj: Apoptosis. 21:351-364
ISSN: 1573-675X
1360-8185
Popis: In this study, we demonstrated that survivin downregulation with TRAIL expression greatly enhanced the cytotoxic death of pancreatic cancer cells after gemcitabine treatment. Using real-time RT-PCR, we analyzed five survivin shRNAs to identify the best target sequence for suppression of human survivin, with the goal of treating gemcitabine-resistant pancreatic cancer cells. Survivin shRNA 5, corresponding to target 5, showed the greatest reduction in survivin mRNA levels. Furthermore, combined treatment with survivin shRNA-expressing adenovirus with gemcitabine plus TRAIL decreased uncleaved PARP and increased consequent PARP cleavage, which was correlated with the greatest levels of survivin downregulation and cell death. These results indicate that survivin functions as a common mediator of gemcitabine- and TRAIL-induced cell death. Using a nude mouse model implanted with MiaPaCa-2 pancreatic cancer cells, we observed tumor regression induced by an oncolytic adenovirus expressing survivin shRNA and TRAIL plus gemcitabine. Together, our findings provide a strong rationale for treating pancreatic cancer patients with both gemcitabine and oncolytic adenovirus armed with survivin shRNA and TRAIL.
Databáze: OpenAIRE
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