Combination of DESI2 and IP10 gene therapy significantly improves therapeutic efficacy against murine carcinoma

Abstract

DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex. We found that, in vitro, the combination of DESI2 and IP10 more efficiently inhibited proliferation of CT26, LL2, SKOV3 and A549 cancer cells via apoptosis. In vivo, the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice. Mechanistically, the augmented antitumor activity in vivo was associated with induction of apoptosis and inhibition of angiogenesis. The anti-angiogenesis was further mimicked by inhibiting proliferation of immortalized HUVEC cells in vitro. Meanwhile, the infiltration of lymphocytes also contributed to the enhanced antitumor effects. Depletion of CD8+ T lymphocytes significantly abrogated the antitumor activity, whereas depletion of CD4+ T cells or NK cells showed partial abrogation. Our data suggest that the combined gene therapy of DESI2 and IP10 can significantly enhance the antitumor activity as apoptosis inducer, angiogenesis inhibitor and immune response initiator. The present study may provide a novel and effective method for treating cancer.