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Phlorotannins have been reported to demonstrate several biological properties, including antioxidant activity, and activities useful in the treatment of diabetic complications and in chemoprevention of several vascular diseases. In this study, we focused on the apoptosis induced by dieckol, a marine algal phlorotannin isolated from Ecklonia stolonifera, on human hepatocellular carcinoma (HCC) Hep3B cells. Dieckol reduced the numbers of viable cells and increased the numbers of apoptotic cells in a dose-dependent manner. Immunoblotting analysis revealed that dieckol increased the expression levels of cleaved caspases-3, 7, 8, and 9, and cleaved poly(ADP-ribose) polymerase. Dieckol increased the permeability of mitochondrial membranes and the release of cytochrome c from mitochondria into the cytosol with apoptosis-inducing factor. In addition, dieckol induced increased expression of truncated Bid and Bim. The results indicate that dieckol induces apoptosis via the activation of both death receptor and mitochondrial-dependent pathways in HCC Hep3B cells.

Anacardic acid (AA, 2-hydroxy-6-pentadecylbenzoic acid), a constituent of the cashew-nut shell, has a variety of beneficial effects on the treatment of cancer and tumors. However, the fact that AA induces ER stress and autophagy in cancer cell is not known. We investigated the effect of AA on ER-stress and autophagy-induced cell death in cancer cells. Because of our interest in lung cancer, we used the non-small cell lung adenocarcinoma A549 cells treated with 3.0 μg/ml of AA for this research. In this research we found that AA induces intracellular Ca(2+) mobilization and ER stress. AA induced the ER stress-inducing factors, especially IRE1α, and the hallmarks of UPR, Grp78/Bip and GADD153/CHOP. AA inhibited the expression of p-PERK and its downstream substrate, p-elF2α. We also demonstrated that AA induces autophagy. Up-regulation of autophagy-related genes and the appearance of autophagosome in transfected cells with green fluorescent protein (GFP)-LC3 and GFP-Beclin1 plasmids showed the induction of autophagy in AA-treated A549 cells. The morphological analysis of intracellular organelles by TEM also showed the evidence that AA induces ER stress and autophagy. For the first time, our research showed that AA induces ER stress and autophagy in cancer cells.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases and is highly resistant to conventional chemotherapy. Therefore, HCC requires more effective prevention and treatment strategies. 5-fluorouracil (5-FU) remains the most widely used chemotherapeutic drug for the treatment of gastrointestinal, breast, head and neck, and ovarian cancers. In pursuit of a novel effective strategy, we have evaluated the potential of 5-FU to promote endoplasmic reticulum (ER) stress and autophagy in Sk-Hep1 HCC cells. We found that 5-FU profoundly induces ER stress in Sk-Hep1 cells and upregulates p53 and activates CHOP/GADD153 and caspase-12. Activation of CHOP/GADD153 and caspase-12 promotes mitochondrial cell death in Sk-Hep1 cells followed by ER stress. Changes in calcium homeostasis and the protein folding machinery cause stress in the ER, leading to apoptotic cell death. Stress in the ER activates autophagy to remove the misfolded protein aggregates and recover from the stress environment. Our study demonstrates that 5-FU-induced ER stress suppresses autophagy and also downregulates GRP78 expression. Activation of autophagy followed by ER stress facilitates the cell survival response. Therefore, the inhibition of protective autophagy may provide a useful pharmacological target. Taken together, these results indicate that 5-FU-induced ER stress activates the mitochondrial apoptotic cell death pathway by downregulating GRP78 and protective autophagy proteins in Sk-Hep1 cells, raising the possibility of using 5-FU as a therapeutic agent to target human HCC.