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.

Histone Deacetylase Inhibitors Interact with Melanoma Differentiation Associated-7/Interleukin-24 to Kill Primary Human Glioblastoma Cells

“…5B). These data are similar to prior studies in prostate cancer cells using the BCL-2 family inhibitor sabutoclax Azab et al, 2012).…”

“…Similar strategies were used to generate Ad.5/3-cytomegalovirus (cmv)-E1A-mda-7 and Ad.5/3-PEG-mda-7. The viruses were expanded and titers determined as previously described elsewhere Dash et al, 2011;Azab et al, 2012).…”

Reversing Translational Suppression and Induction of Toxicity in Pancreatic Cancer Cells Using a Chemoprevention Gene Therapy Approach

“…Level of significance: *P , 0.05; **P , 0.01; ***P , 0.001. et al, 2010b;Azab et al, 2012Azab et al, , 2014. Western blotting showed similar results, with Ad.5/3-mda-7 inducing greater MDA-7/IL-24 protein expression, both with and without the addition of D-limonene compared with Ad.5-mda-7 (Fig.…”

“…The creation of Ad.5/3 chimeric Ad combines both of these serotypes to create a virus that is capable of using CAR, CD46, and/or desmoglein for infection. We demonstrated that Ad.5/3-mda-7 is able to infect prostate, renal, glioblastoma multiforme, and colorectal cancer cells with greater efficiency compared with Ad.5-mda-7 and that this translates into greater toxicity (Dash et al, 2010b(Dash et al, , 2011Eulitt et al, 2010;Hamed et al, 2010;Azab et al, 2012).…”

“…Unfortunately, cancer cells, including pancreatic cancer cells, often downregulate these receptors, which leads to inefficient viral infectivity (Pearson et al, 1999). Using alternate viral serotypes to create chimeric viruses can help with this issue (Dash et al, 2010b(Dash et al, , 2011Hamed et al, 2010Hamed et al, , 2013Azab et al, 2012Azab et al, , 2014. The Ad.3 serotype relies on expression of CD46 and desmoglein for viral entry into cells .…”