(-)-Agelasidine A Induces Endoplasmic Reticulum Stress-Dependent Apoptosis in Human Hepatocellular Carcinoma.

Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

Proton Pump Inhibitor Use is Associated With Risk of Pancreatic Cancer: A Nested Case-Control Study.

PURPOSE: To investigate the use of proton pump inhibitors (PPIs) and the risk of pancreatic cancer. METHODS: A nested case-control analysis was conducted. Patients with pancreas cancer were matched with controls by propensity score. Univariate and multivariate logistic regression models were used to determine whether PPIs use affected the risk of pancreas cancer. Dose effect was analyzed based on the cumulative defined daily dose (DDD), which was calculated using the total supply of PPIs to individual patients in terms of days and quantity. RESULTS: A total of 1087 patients with pancreas cancer were matched with 1087 control patients from the database. The overall adjusted odds ratio (OR) of PPI use associated with pancreas cancer was 1.69 (95% confidence interval [CI], 1.44-2.05). Dose analysis by cumulative DDD, based on all types of PPI combined, revealed a lower adjusted OR of 0.92 (95% CI, 0.64-1.33) for those on <30 cumulative DDD compared with those on ≥150 cumulative DDD, whose adjusted OR was 2.19 (95% CI, 1.68-2.85). Compared with PPI nonusers, the risks of pancreas cancer were: OR 0.89 (95% CI, 0.62-1.27) for patients using PPI <30 days and 2.22 (95% CI, 1.68-2.94) for ≥150 days. CONCLUSIONS: Risk of pancreas cancer was associated with PPI use in patients with peptic ulcer diseases or gastroesophageal reflux disease.