Isoharringtonine Induces Apoptosis of Non-Small Cell Lung Cancer Cells in Tumorspheroids via the Intrinsic Pathway

Lung Cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D Cell Culture system. On the Other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced Apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an Orphan Nuclear Receptor known to regulate proliferation and Apoptosis of Cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced Cancer cell death in A549 tumorspheroids by activating the intrinsic Apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes Cancer cells to anti-cancer treatment.