Enhanced in-vitro and in-vivo suppression of A375 melanoma by combined IL-24/OSM adenoviral-mediated gene therapy

Interleukin-24 (IL-24)/melanoma differentiation-associated gene-7 (mda-7) is a unique cytokine-tumor suppressor that displays ubiquitous antitumor properties and tumor-specific killing activity. Oncostatin M (OSM) is the most active IL-6-type cytokine and inhibits the proliferation of various solid tumor cell lines. Multigene-based combination therapy may be an effective practice in cancer gene therapy. The therapeutic potential of a combination of IL-24 and OSM in treating cancers is still elusive. In this study, we aimed to examine the enhanced antitumor activity of adenovirus-mediated IL-24/OSM tumor suppressor gene cotransfer in human melanoma cells. We constructed an IL-24/OSM bicistronic adenovirus and assessed its combined effect on A375 human melanoma cells in vitro and in vivo by detecting and comparing apoptosis in the bicistronic antioncogene group (Ad-IL-24-OSM) and in the IL-24 or OSM single antioncogene group. We also investigated the possible mechanism underlying this effect. The bicistronic adenovirus-mediated coexpression of IL-24 and OSM induced additive growth suppression and apoptosis and an overlapping effect on the upregulation of p21, p53, Bax, and cleaved caspase-3 in vitro and in vivo. Moreover, Ad-IL-24-OSM treatment additively reduced the expression of CDK4 and cyclin D1 in A375 melanoma cells and the expression of CD34 and Cox-2 in A375 xenograft tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-IL-24-OSM was closely associated with the activation of the apoptotic pathway and the additive inhibition of tumor angiogenesis. Therefore, our results indicate that cancer gene therapy combining two or more tumor suppressors, such as IL-24 and OSM, may constitute a novel and effective therapeutic strategy for treating malignant melanoma and other cancers. (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.