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.

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.

• Authors: 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
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 227 Issue 5 Pg. 2145-53 (May 2012) ISSN: 1097-4652 [Electronic] United States
• PMID: 21780116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• 1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide
• CLMP protein, human
• CLMP protein, mouse
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Interleukins
• Receptors, Virus
• apogossypol
• interleukin-24
• Gossypol

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, pathology)
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Drug Synergism
• Gene Transfer Techniques
• Gossypol (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Humans
• Interleukins (genetics, metabolism)
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy, pathology)
• Receptors, Virus (genetics, metabolism)
• Transgenes
• Treatment Outcome
• Xenograft Model Antitumor Assays