The renin-angiotensin system blockers as adjunctive therapy for cancer: a meta-analysis of survival outcome.

OBJECTIVE: The renin-angiotensin system blockers (RASBs), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are widely used to reduce cardiovascular disease (CVD) events. Accumulating pre-clinical and clinical studies suggested that RASBs possesses anti-carcinogenic properties, and their use is associated with favorable outcomes in several type cancers. To conduct a meta-analysis to evaluate the effect of adjunctive therapy of renin-angiotensin system blockers combined with chemotherapeutic agents in cancer patients. MATERIALS AND METHODS: Data from a total of 2436 patients from 7 retrospective studies investigating chemotherapeutic agents in combination with RASBs agents versus chemotherapeutic agents were included in this meta-analysis. Publication bias was assessed by the Begg's Test, Egger's test and funnel plot. Subgroup analysis was conducted when the chemotherapeutic agents were the same. RESULTS: A significant reduction in overall mortality in favor of chemotherapeutic agents in combination with RASBs agents was observed, hazard ratio (HR) 0.80 (95% CI: 0.69-0.92); there was a significant decrease in the risk of disease progression in favor of chemotherapeutic agents in combination with RASBs regimens, HR 0.79 (95% CI: 0.66-0.94), compared with those who only used chemotherapeutic agents. Subgroup analysis indicated that platinum-based agents plus ACEI/ARB could increase significantly the survival outcome (HR = 0.56; 95% CI: 0.38-0.82). CONCLUSIONS: Our results suggest that RASBs combined with chemotherapeutic agents may improve outcomes in multiple types' cancer patients. More research and well-designed, rigorous, large clinical trials are required to address these issues.

The cancer-associated fibroblasts and drug resistance.

The present treatment of solid tumors is plagued by drug resistance. Despite continued development of meticulously designed therapeutic scheme, cancer cells remain poorly being completely eliminated. Because therapeutic resistance is a problem with the drug used in cancer therapy, most of the studies about the drugs resistance have focused on the role of epithelial cancer cells themselves. However, it is becoming increasingly apparent that tumor microenvironment could provide a shelter for tumor cells which keep their survival after initial drug exposure. Cancer-associated fibroblasts (CAFs) are the crucial component of the tumor microenvironment; substantial evidence suggests that the CAFs mediate resistance of solid tumor cells to the anticancer drugs. In this review, we describe how the CAFs may be involved in the resistance of tumor cells to the therapeutic agents and present some of the emerging therapeutic targets for modulation this resistant phenotype.

Endogenous nitric oxide induces activation of apoptosis signal-regulating kinase 1 via S-nitrosylation in rat hippocampus during cerebral ischemia-reperfusion.

Apoptosis signal-regulating kinase 1 (ASK1) is a general mediator of cell death in response to a variety of stimuli, including reactive oxygen species, tumor necrosis factor α, lipopolysaccharide, endoplasmic reticulum stress, calcium influx and ischemia. Here we reported ASK1 was activated by nitric oxide (NO) through S-nitrosylation during cerebral ischemia-reperfusion. The reagents that abrogate neuronal nitric oxide synthase (nNOS) activity such as nNOS inhibitor 7NI and N-methyl-D-aspartate receptor antagonist MK801 prevented ASK1 activation via decreasing ASK1 S-nitrosylation. In HEK293 cells, over-expressed ASK1 could be S-nitrosylated by both exogenous and endogenous NO and Cys869 was identified as the site of ASK1 S-nitrosylation. S-nitrosylation increased the level of ASK1 phosphorylation at Thr845, which represents ASK1 activation. Our results further confirmed that S-nitrosylation led to the increment of ASK1 dimerization. S-nitrosylation of ASK1 also activated the downstream JNK signaling and JNK-mediated nucleic pathway. The exogenous NO (SNP and GSNO) reversed the effect of endogenous NO by suppressing S-nitrosylation of ASK1 and exerted neuroprotection during ischemia-reperfusion. These results suggest that inhibiting ASK1 S-nitrosylation may be a novel approach for stroke therapy.