The Nf-κb Inhibitor Imd-0354 Targets Human Non-Small Cell Lung Cancer Stem Cells and Combined with Chemotherapy Reduces Multidrug Resistance

Abstract

Most lung cancer patients are diagnosed at an advanced stage, when prognosis is poor. Multidrug resistance and tumor recurrence have been major reasons for these patients to succumb to the disease. Recent evidence points to cancer stem cells as being responsible for multidrug resistance and tumor repopulation as a result of their increased drug efflux and other stem cell-like properties. Thus, recent efforts have focused on targeting these cancer stem cells. Here, we combined liposomal nanoparticles targeted with a legumain inhibitor as a safe vehicle for drug delivery to the tumor microenvironment with Doxorubicin, a common chemotherapeutic agent that targets bulk cancer cells, and IMD-0354, an inhibitor of NF-κB targeting cancer stem cells. IMD-0354 decreased side populations, ABC transporters, stem-like and apoptosis resistance genes, and colony formation of human non-small cell lung cancer cells. In addition, IMD-0354 also had a cytotoxic effect on non-cancer stem cells and increased their apoptosis. The targeted delivery method used previously in syngeneic mouse models enhanced drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Further, such targeted delivery reduced in vivo tumor burden in an aggressive model of human non-small cell lung cancer xenografts. Targeting of both bulk tumor cells and cancer stem cells with IMD-0354 as an adjuvant for chemotherapy are likely to reduce multidrug resistance and tumor recurrence, and thereby significantly reduce patient death from non-small cell lung cancer.