In vitro and in vivo anticancer activity of Lycorine in prostate cancer by inhibiting NF-κB signaling pathway

Abstract

NF-κB transcription factors critically regulate the expression of genes which are involved in important cellular processes, including cellular proliferation and apoptosis. Abnormal activation of the NF-κB signaling pathway has been implicated in a variety of human cancers. Hyper-activation of the NF-κB signaling pathway has been found to lead to tumor survival, anti-apoptosis and invasion in the development of prostate cancer. In the present work, we identified Lycorine as a potent NF-κB inhibitor using a NF-κB activity dependent luciferase reporter in PC3 and DU145 prostate cancer cells. With this reporter gene assay, we found that Lycorine significantly suppressed the constitutive NF-κB activity as well as the NF-κB activity induced by TNF-α, LPS, PMA and IL-1β. Western blotting analysis of the NF-κB signaling pathway further showed that Lycorine inhibited IκB-α (inhibitor of κB) phosphorylation, IκB-α degradation, and p65 phosphorylation. Consistent with this, the subsequent nuclear translocation of p65 was blocked by Lycorine as evidenced in the immunofluorescence assay and western blotting. Furthermore, we observed that cell cycle was arrested at G2/M in Lycorine treated cells using FACS analysis. Western blotting analysis indicated that Lycorine increased the expression of Cyclin D1 but decreased the expression of p21. In addition, FACS analysis showed that Lycorine induced apoptosis in DU145 and PC3 cells. Western blotting analysis revealed that Lycorine decreased the expression of anti-apoptosis genes myc, survivin and Bcl-2 while increased cleavage of PARP. Finally, we observed a significant anticancer effect of Lycorine in a RM-1 prostate cancer xenograft mouse model. In agreement with its in vitro anticancer effect, Lycorine inhibited p65 phosphorylation, IKK-β phosphorylation and the expression of Ki-67, while increased the cleavage of Caspase 3 in tumor tissue. Taken together, our data demonstrated the in vitro and in vivo anti-prostate cancer activity of Lycorine by inhibiting the NF-κB signaling pathway, and highlighted it as a lead compound for further development into an effective anticancer drug.

Alleviating effect of lycorine on CFA‑induced arthritic pain via inhibition of spinal inflammation and oxidative stress

“…In a model of inflammatory pain, intrathecal pretreatment with NF-κB inhibitors, namely, NF-κB decoy or pyrrolidine dithiocarbamate, reduced mechanical allodynia, and thermal hyperalgesia (55). Lycorine inhibited NF-κB signaling activity, IκB-α phosphorylation/degradation and p65 phosphorylation in prostate cancer cells and a mouse model (56). Lycorine decreased the levels of inflammatory cytokines and MDA levels by attenuating the activity of the high-mobility group box 1/Toll-like receptors/NF-κB pathway in a model of lung injury that utilizes LPS (57).…”

Role of Metabolism and Metabolic Pathways in Prostate Cancer

“…In addition to inducing metabolic reprogramming of PCa cells via activation of genes for glucose absorption and metabolism [ 169 , 190 ], the p52 subunit can also stimulate AR signaling, which adds to androgen-independent proliferation [ 191 , 192 ]. But there may be yet another layer of crosstalk between NF-κB and AR, as the classical IKKα and IKKβ upstream of NF-κB may also effectively regulate AR activation through phosphorylation [ 193 , 194 , 195 , 196 , 197 , 198 ].…”

Benzoindolizidine Alkaloids Tylophorine and Lycorine and Their Analogues with Antiviral, Anti-Inflammatory, and Anticancer Properties: Promises and Challenges

“…Over the years, the anticancer power of lycorine and its derivatives has been reported in diverse in vitro and in vivo cancer models [117][118][119][120][121][122][123][124][125][126][127][128]. It has also been found to affect cell proliferation in drug-resistant cancer cells [69,124,129].…”

“…It has also been found to affect cell proliferation in drug-resistant cancer cells [69,124,129]. A modulation of signal transducer and activator of transcription 3 (STAT3) protein, RNA binding motif 10 (RBM10), NF-κB, and the E3 ubiquitin ligase NEDD4-1 (neural precursor cell expressed developmentally down-regulated protein 4-1), along with the induction of apoptosis and cell cycle arrest, have been associated with its anticancer properties [123,130,131]. Its power has been considered promising in cancer research, although further studies are needed to better understand its mechanisms of action and clinical efficacy.…”