Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells

Belal Azab, Rupesh Dash, Swadesh K. Das, Sujit K. Bhutia, Xue Ning Shen, Bridget A. Quinn, Siddik Sarkar, Xiang Yang Wang, Michael Hedvat, Igor P. Dmitriev, David T. Curiel, Steven Grant, Paul Dent, John C. Reed, Maurizio Pellecchia, Devanand Sarkar, Paul B. Fisher

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3-mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients.

Original languageEnglish
Pages (from-to)2145-2153
Number of pages9
JournalJournal of Cellular Physiology
Volume227
Issue number5
DOIs
StatePublished - May 1 2012

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    Azab, B., Dash, R., Das, S. K., Bhutia, S. K., Shen, X. N., Quinn, B. A., Sarkar, S., Wang, X. Y., Hedvat, M., Dmitriev, I. P., Curiel, D. T., Grant, S., Dent, P., Reed, J. C., Pellecchia, M., Sarkar, D., & Fisher, P. B. (2012). Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells. Journal of Cellular Physiology, 227(5), 2145-2153. https://doi.org/10.1002/jcp.22947