Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI–LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2α dephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidant α-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.
The present study was designed to determine the possible protective and therapeutic effects of olive oil and/or Ficus carica against radiation-induced cytological and histological changes in liver and Kidney of male albino rats. Irradiation was performed by whole-body exposure of rats to an acute single dose gamma radiation of 6 Gy. Irradiated rats received, via gavage, extra virgin olive oil (7.6 ml/kg b.wt), and/or extract of Ficus carica fruit (1 g/kg b.wt) before and/or after radiation exposure. Six rats were sacrificed on the 1 st and 15 th -day post-irradiation exposure at the control and treated irradiated subgroups. Time duration for this experiment was one month.The γ-Irradiation treated group revealedhisto pathological alterations in the hepatic and renal tissues on the 1 st and 15 th -day post-irradiation as compared to the control rats. The administration of the olive oil and/or Ficus carica showed beneficial results against the deleterious effects of γ-irradiation. A better ameliorative effect was noticed with the combined treatments that revealed the synergistic effect between them.In conclusion, the administration of the olive oil and/or Ficus carica provides considerable radioprotective and radiotherapeutic effects against whole body γ-radiation in male Wistar albino rats.
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