Conditionally replicative adenovirus-based mda-7/IL-24 expression enhances sensitivity of colon cancer cells to 5-fluorouracil and doxorubicin.

Abstract

BACKGROUND:

Multiple drug resistance (MDR) greatly limits the efficacy of chemotherapy for colon cancer. An adenovirus armed with Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24; abbreviated to 'IL-24' here) was shown to reverse the MDR of colon cancer cells to oxaliplatin and doxorubicin. However, the relatively low expression level of IL-24 mediated by a replication-deficient adenoviral vector hindered its clinical application.

METHODS:

To enhance IL-24-dependentreversion of the MDR phenotype, we utilized a conditionally replicative adenoviral vector, AdBB-IL24, to express IL-24 at a high level for more efficient MDR reversion.

RESULTS:

An enzyme-linked immunosorbent assay (ELISA) suggested conditionally replicative adenoviral vector-mediated IL-24 expression was elevated in comparison with that of a replication-deficient adenoviral vector, Ad-IL24. AdBB-IL24 was shown to reverse MDR in colon cancer cells more potently than Ad-IL24. The AdBB-IL24-induced MDR reversion was linked to reduced P-glycoprotein (Pgp) and breast cancer resistance protein 1 (BCRP1) expression. Consistently, 5-fluorouracil and doxorubicin induced more apoptosis in AdBB-IL24-infected colon cancer cells compared with that in the Ad-IL24-infected cells. A cell viability assay showed that AdBB-IL24 could enhance the growth-inhibitory effect of 5-fluorouracil and doxorubicin on colon cancer cells more effectively than Ad-IL24 in vitro. In a mouse model, we also found that the combination of 5-fluorouracil and doxorubicin with AdBB-IL24 completely inhibited the growth of colon cancer cells.

CONCLUSION:

We here provide evidence supporting conditionally replicative adenoviral vector-based gene therapy as a powerful strategy to enhance mda7/IL-24-dependent MDR reversion of colon cancer cells.

• Authors: Jing Xu, Yiwo Mo, Xiaoyun Wang, Jun Liu, Xinjin Zhang, Junfeng Wang, Lei Hu, Chao Yang, Lei Chen, Yankun Wang
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 48 Issue 2 Pg. 203-13 (Feb 2013) ISSN: 1435-5922 [Electronic] Japan
• PMID: 22820863 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Interleukins
• Neoplasm Proteins
• interleukin-24
• Doxorubicin
• Fluorouracil

Topics

• Adenoviridae (genetics, physiology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Combined Modality Therapy
• Doxorubicin (administration & dosage, pharmacology, therapeutic use)
• Drug Resistance, Multiple (genetics)
• Drug Resistance, Neoplasm (genetics)
• Fluorouracil (administration & dosage, pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Interleukins (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Neoplasm Proteins (biosynthesis, genetics)
• Virus Replication (drug effects)
• Xenograft Model Antitumor Assays