A conditionally replicating adenovirus expressing IL-24 acts synergistically with temozolomide to enhance apoptosis in melanoma cells in vitro

摘要

Malignant melanoma is characterized by suppressed apoptosis in tumor cells and high levels of invasion. Temozolomide (TMZ) is one of the most effective single chemotherapeutic agents for patients with malignant melanoma, but resistance develops quickly and frequently. Therapeutic cytokines such as interleukin-24 (IL-24) and conditionally replicating adenoviruses have exhibited promising results as complementary therapies. Thus, the present study hypothesized that a conditionally replicating adenovirus expressing IL-24 combined with TMZ may exhibit increased antitumor activity compared with either treatment alone in melanoma A375 and M14 cell lines in vitro. The present study constructed an E1B-55 gene-deleted conditionally replicating adenovirus expressing the IL-24 gene (ZD55-IL-24). IL-24 was expressed at high levels in melanoma cells infected with ZD55-IL-24 in the presence of TMZ. The combination of ZD55-IL-24 + TMZ induced higher protein expression levels of the proapoptotic proteins B-cell lymphoma-2 (Bcl-2)-like protein 4 and phosphorylated protein, γ-H2A histone family member X (γ-H2AX), and reduced the levels of the antiapoptotic proteins Bcl-2, myeloid cell leukemia-1and nuclear factor-κB compared with either treatment individually. A dose-dependent increase in the cytopathic effects for the combination of ZD55-IL-24 and TMZ was also observed. The data of the present study suggest that the ZD55-IL-24 + TMZ combination induced increased levels of apoptosis, possibly by triggering DNA damage, in melanoma cells in vitro compared with either treatment alone. These findings suggest that this strategy may be a promising approach for the treatment of patients with malignant melanoma.