Silymarin inhibits the progression of Ehrlich solid tumor via targeting molecular pathways of cell death, proliferation, angiogenesis, and metastasis in female mice.

BACKGROUND: Plant-derived phytochemicals have been reported to exert anticancer activity. This study investigated the antitumor role of silymarin (Silybum marianum) (SMN) and its molecular targets in Ehrlich solid tumor xenografts in vivo. METHODS AND RESULTS: Female Swiss albino mice were divided into three groups (of five animals each) that were engrafted with Ehrlich tumor (ET) cells with or without SMN treatment. The 3rd groups treated with DMSO only vehicle control group. A significant reduction in animal body mass and tumor volume/weight were observed in xenografted mice treated with SMN. SMN modulated oxidative stress in tumors while enhancing the antioxidant levels in mouse serum. SMN activated both mitochondrial and death receptor-related apoptosis pathways and induced cell cycle arrest, marked by a significant downregulation of cyclin D1 in SMN-treated tumors. Significant decreases in RNA content and protein expression levels of Ki-67 and proliferating cell nuclear antigen were observed in ET cells. Additionally, SMN downregulated vascular endothelial growth factor and nuclear factor-kappa B levels indicating anti-angiogenesis activity of this agent. SMN upregulated the expression of E-cadherin in tumor tissue suggesting, that SMN has potential ability to inhibit metastasis. Tumor tissue from SMN-treated animals showed a remarkable degeneration and reduction in the neoplastic cell density. CONCLUSIONS: The anticancer effect was associated with apparent apoptosis in neoplastic cells with abundance of multifocal necrotic areas. SMN was found to inhibit ET growth via enhancing apoptosis, inhibition of cell division and reduction in angiogenesis in vivo. Hypothetical scheme of SMN antitumor effects (mechanism of signaling) in solid ET in vivo. SMN anticancer effect may be mediated by molecular mediators that affect proliferation, cell cycle activity, apoptotic pathways, angiogenesis, and metastasis.

ß-caryophyllene oxide induces apoptosis and inhibits proliferation of A549 lung cancer cells.

One of the most common cancers that result in death is lung cancer. There is new hope in the fight against lung cancer thanks to the chemopreventive properties of natural dietary substances like ß-caryophyllene oxide (CPO), and research is currently being done to test this theory. CPO, a sesquiterpene isolated from medicinal plant essential oils, inhibits carcinogenesis and has been effective in treating many cancers. This study examined how CPO affected proliferation of human lung cancer A549 cells. CPO was found to have an inhibitory concentration (IC50) of 124.1 g/ml. The proliferative markers Ki67 and PCNA were significantly inhibited after cells were treated with CPO at a concentration of 50 g/ml compared to controls. CPO-treated cells expressed more P21, P53, and DNA strand breaks than controls. This was accompanied by a significant cell cycle arrest in the S and G2/M phases. In treated A549 cells, this was also associated with a significant induction of apoptosis, as shown by the upregulation of the expression of caspases 3, 7, and 9, as well as Bax, and the downregulation of Bcl-2. Furthermore, the redox status of treated A549 cells revealed a marked rise in GSH and GPx activity levels and a decline in 4-HNE levels, indicating low oxidative stress following CPO treatment of A549 cells. In conclusion, cell cycle arrest and apoptosis, which are unrelated to oxidative stress, were the mechanisms by which CPO reduced cancer lung cell growth. This finding might be a potential therapeutic target for the treatment of lung cancer. Hypothetical scheme of CPO anticancer effects (mechanism of signaling) in A549 cells; in vitro. CPO treatment increases expression of p21, p53 and DNA fragmentation. These events cause arrest of cell cycle which was associated with significant induction in apoptosis via increase expression of caspases (-3,-7,-9), and Bax and downregulation of Bcl-2.

Melatonin exerts a neuroprotective effect against γ-radiation-induced brain injury in the rat through the modulation of neurotransmitters, inflammatory cytokines, oxidative stress, and apoptosis.

The current study aimed to investigate the ameliorative effect of melatonin (MLT) against brain injury in rats undergoing whole-body exposure to γ-radiation. Male Wistar rats were whole-body exposed to 4-Gy γ-radiation from a cesium-137 source. MLT (10 mg/kg) was orally administrated 30 minutes before irradiation and continued once daily for 1 and 7 days after exposure. In the irradiated rats, the plasma levels of glutamate were increased, while the gamma-aminobutyric acid (GABA) levels were decreased, and MLT improved the disturbed glutamate and GABA levels. These effects paralleled an increase in pro-inflammatory cytokines (IL-1b, IL-6, and TNF-a) and C-reactive protein as well as a decrease in IL-10 in the plasma of the irradiated rats. MLT treatment markedly reduced these effects, indicating its anti-inflammatory impact. Immunohistochemical studies demonstrated a remarkable upregulation of caspase-3 and P53 expression, indicating the increased apoptosis in the brain of irradiated rats. MLT significantly downregulated the expression of these parameters compared with that in the irradiated rats, indicating its anti-apoptotic effect. Oxidative stress is developed in the brain as evidenced by increased levels of malondialdehyde; decreased activities of superoxide dismutase, catalase, and glutathione peroxidase; and decreased content of glutathione in the brain. MLT remarkably ameliorated the development of oxidative stress in the brain of the irradiated rats indicating its antioxidant impact. The histopathological results were consistent with the biochemical and immunohistochemical results and showed that MLT remarkably protected the histological structure of brain tissue compared with that in the irradiated rats. In conclusion, MLT showed potential neuroprotective properties by increasing the release of neurotransmitters, antioxidants, and anti-inflammatory factors and reducing pro-inflammatory cytokines and apoptosis in the brain of irradiated rats. MLT can be beneficial in clinical and occupational settings requiring radiation exposure; however, additional studies are required to elucidate its neuroprotective effect in humans.