An oncolytic adenovirus expressing interleukin-24 enhances antitumor activities in combination with paclitaxel in breast cancer cells

Abstract

Oncolytic adenoviruses are a novel class of anticancer treatment, based upon their ability to replicate selectively within malignant cells resulting in cell lysis. The replication-selective adenovirus, ZD55-IL-24, was constructed by harboring an E1B-55 kDa deletion and arming with interleukin-24 (IL-24). The microtubule-stabilizing drug paclitaxel (PTX) exhibits activity in relapsed cancer. In the present study, the synergistic antitumor effects of the combination of PTX and ZD55-IL-24 on breast cancer cells was investigated. The results demonstrated that there were different roles for PTX in the expression of transgenic mRNA and protein. ZD55-IL-24 combined with PTX induced marked growth inhibition of MDA-MB-231 and Bcap-37 cells. PTX increased viral uptake and appeared not to alter the replication of ZD55-IL-24 in breast cancer cells. Annexin V-fluorescein isothiocyanate/propidium iodide staining and the Hoechst 33258 assay indicated that ZD55-IL-24 induced an increase in the number of apoptotic cells when administered in combination with PTX. It was demonstrated that ZD55-IL-24 conjugated with PTX was highly concomitant, and increased proapoptotic proteins levels, activated caspase-3, -7 and -9 and down-regulated anti-apoptotic proteins. These results suggested that ZD55-IL-24 in combination with PTX exhibited a markedly increased cytotoxic and apoptosis-inducing effect in breast cancer cells. Thus, this chemo-gene-viro therapeutic strategy was demonstrated to be superior to conventional chemotherapy or gene-viro therapy alone.