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

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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.

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Conflict of interest

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The First People’s Hospital of Yunnan Province, Kunhua Hospital Affiliated to Kunming Medical College, Kunming, China

    Jing Xu, Yiwo Mo, Xiaoyun Wang, Jun Liu, Xinjin Zhang, Junfeng Wang, Lei Hu, Chao Yang, Lei Chen & Yankun Wang

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  1. Jing Xu
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  2. Yiwo Mo
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  3. Xiaoyun Wang
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  4. Jun Liu
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  5. Xinjin Zhang
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  7. Lei Hu
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  10. Yankun Wang
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Corresponding author

Correspondence to Yankun Wang.

Additional information

J. Xu and Y. Mo contributed equally to this work.

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Xu, J., Mo, Y., Wang, X. et al. Conditionally replicative adenovirus-based mda-7/IL-24 expression enhances sensitivity of colon cancer cells to 5-fluorouracil and doxorubicin. J Gastroenterol 48, 203–213 (2013). https://doi.org/10.1007/s00535-012-0623-y

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  • DOI: https://doi.org/10.1007/s00535-012-0623-y

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