Regulation of cytotoxicity and apoptosis-associated pathways contributes to the enhancement of efficacy of cisplatin by baicalein adjuvant in human A549 lung cancer cells.

Scutellaria baicalensis (SB; Chinese name, huangqin) is widely used in Chinese medicine as a traditional adjuvant in the chemotherapy of lung and liver cancer. Baicalein is one of the bioactive flavonoid components isolated from the root of SB. The present study aimed to observe the effect of baicalein, in combination with platin-based systemic chemotherapy (cisplatin), on cytotoxicity and apoptosis of human A549 lung cancer cells. The cell cultures were treated with baicalein, cisplatin, or a combination of the two. Cell viability and cytotoxicity was assayed by XTT, and cell apoptosis was measured by flow cytometry. The apoptosis-associated proteins were detected by western blot analysis. The cytokines in the culture supernatant were detected by ELISA. The present study revealed that cisplatin and the baicalein-cisplatin combination inhibited viability and promoted cytotoxicity of A549 cells. Cisplatin, baicalein and baicalein-cisplatin combination treatments were effective in the promotion of apoptosis of A549 cells. Baicalein and baicalein-cisplatin combination treatments also inhibited B cell lymphoma-2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) expression. Additionally, cisplatin, baicalein and the baicalein-cisplatin combination promoted caspase-3 expression. Furthermore, the baicalein-cisplatin combination suppressed the secretion of interleukin-6, and baicalein and the combination of baicalein cisplatin decreased the secretion of tumor necrosis factor-α of A549 cells. The present study concluded that baicalein combined with cisplatin induced cytotoxicity and apoptosis of A549 cells, and such activity may be associated with the regulation of Bcl-2, Bax and caspase-3, indicating a promising alternative method for lung cancer.

Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction.

The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1 beta renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1 beta compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ERK, but not PLC gamma, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1 beta. As the cytokine did not influence TrkB receptor and PLC gamma activation, IL-1 beta might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1 beta suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1 beta places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism.

Interleukin-1beta interferes with signal transduction induced by neurotrophin-3 in cortical neurons.

It was previously observed that IL-1beta interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1beta reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1beta in BDNF-induced signal transduction. The functional consequences of the effect of IL-1beta on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1beta levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.