Abstract
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.
Highlights
Lung cancer is one of the most frequently diagnosed types of cancer and is the leading cause of cancer-associated death worldwide [1]
We examined the growth properties of A549 and NCI-H460 tumorspheroids in comparison to those of A549 and NCI-H460 cells grown in a 2D culture
In a 3D culture system, NCI-H460 tumorspheroids grew fast from a diameter of 288.5 ± 14.1 μm to that of 537.2 ± 7.1 μm over 4 days (Figure 1C,D)
Summary
Lung cancer is one of the most frequently diagnosed types of cancer and is the leading cause of cancer-associated death worldwide [1]. Most NSCLC patients are diagnosed in an advanced stage due to difficulties with early detection, and the common treatment options include cytotoxic chemotherapy, target therapy, and immunotherapy [2,4,5]. Isoharringtonine (IHT), one of the most effective natural products, is an alkaloid extracted from the leaves of Cephalotaxus koreana Nakai. Alkaloids extracted from Cephalotaxus harringtonia have been reported to have anti-tumor activity against murine leukemia cells [9,10]; among them, harringtonine, IHT, and homoharringtonine were shown to inhibit protein synthesis [11,12,13]. Homoharringtonine and IHT have been reported to inhibit transcription factor, signal transducer, and transcription 3 (Stat3) activation in gefitinib-resistant NSCLC and breast cancer cells, respectively [18,19]
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