Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-λ, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD1 1c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.

Similar to human CLL, the de novo NZB mouse model has a genetically determined age-associated increase in malignant B-1 clones and decreased expression of microRNAs miR-15a and miR-16 in B-1 cells. In the present study, lentiviral vectors were employed in vivo to restore miR-15a/16, and both the short-term single injection and long-term multiple injection effects of this delivery were observed in NZB. Control lentivirus without the mir-15a/16 sequence was used for comparison. We found that in vivo lentiviral delivery of mir-15a/16 increased miR-15a/16 expression in cells that were transduced (detected by GFP expression) and sera when compared to control lentivirus treatment. More importantly, mice treated with the miR- expressing lentivirus had decreased disease. The lentivirus had little systemic toxicity while preferentially targeting B-1 cells. Short-term effects on B-1 cells were direct effects and only malignant B-1 cells transduced with miR-15a/16 lentivirus had decreased viability. In contrast, long-term studies suggested both direct and indirect effects resulting from miR-15a/16 lentivirus treatment. A decrease in B-1 cells was found in both the transduced and non-transduced populations. Our data support the potential use of systemic lentiviral delivery of miR-15a/16 to ameliorate disease manifestations of CLL.

Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.

Background Aberrant activation of the NLRP 3 (nucleotide‐binding oligomerization domain, leucine‐rich repeat–containing receptor family pyrin domain‐containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP 3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP 3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP 3 ubiquitination blunts the assembly and activation of the NLRP 3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low‐density lipoprotein receptor– or apolipoprotein E–deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP 3 ubiquitination. We showed that tranilast restricted NLRP 3 oligomerization and inhibited NLRP 3 inflammasome assembly. Tranilast markedly suppressed NLRP 3 inflammasome activation in low‐density lipoprotein receptor– and apolipoprotein E–deficient macrophages. Through reconstitution of the NLRP 3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP 3 inflammasome activation. By adopting different regimens for tranilast treatment of low‐density lipoprotein receptor– and apolipoprotein E–deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP 3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP 3 ubiquitination, blunts the assembly and activation of the NLRP 3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low‐density lipoprotein receptor– and apolipoprotein E–deficient mice.