Ophiopogonin D modulates multiple oncogenic signaling pathways, leading to suppression of proliferation and chemosensitization of human lung cancer cells

Background: Ophiopogonin D (OP-D), a steroidal glycoside obtained from the Chinese medicinal plant Ophiopogonin japonicas (the root portion), has been traditionally used to treat fever, inflammation, cough, sputum etc. However, the detailed molecular mechanism(s) underlying its therapeutic actions is still unknown. Hypothesis: Because nuclear factor-kappa B (NF-kappa B), PI3K/AKT, and activator protein-1 (AP-1) signaling cascades have significant functions in cell proliferation, inflammation, and angiogenesis in tumor cells, we hypothesized that OP-D may disrupt these signaling cascades to exert its anticancer effects in human lung-cancer cells. Methods: We evaluated the effect of OP-D on multiple signaling cascades and its regulated functional responses in lung cancer cells. Results: OP-D blocked both basal and cytokine-induced proliferation of human lung-cancer cells and caused down-regulation of the expression of diverse oncogenic gene products through the suppression of NF-kappa B, PI3K/AKT, and AP-1 pathways; but did not affect JNK, p38 and ERK MAP kinases. Interestingly, OP-D suppressed constitutive NF-kappa B activation in lung cancer cells via interfering with the I kappa B kinase activation, which inhibited phosphorylation and caused degradation of I kappa B-alpha. OP-D also blocked phosphorylation and the nuclear translocation of p65, thereby suppressing NF-kappa B reporter activity in lung cancer cells. Besides, OP-D could augment cell death induced by paclitaxel in lung-cancer cells. Conclusion: Overall, the data indicates that OP-D may abrogate diverse signaling cascades linked to tumorigenesis, and can be used in combination with chemotherapeutic agents for cancer therapy.