Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and the therapeutic options available usually have little impact on survival. Great hope is placed on new therapeutic targets, including long noncoding RNAs (lncRNAs), and on the development of new drugs, based on e.g., broccoli-derived sulforaphane, which meanwhile has shown promise in pilot studies in patients. We examined whether sulforaphane interferes with lncRNA signaling and analyzed five PDAC and two nonmalignant cell lines, patient tissues (n = 30), and online patient data (n = 350). RT-qPCR, Western blotting, MTT, colony formation, transwell and wound healing assays; gene array analysis; bioinformatics; in situ hybridization; immunohistochemistry and xenotransplantation were used. Sulforaphane regulated the expression of all of five examined lncRNAs, but basal expression, biological function and inhibition of H19 were of highest significance. H19 siRNA prevented colony formation, migration, invasion and Smad2 phosphorylation. We identified 103 common sulforaphane- and H19-related target genes and focused to the virus-induced tumor promoter APOBEC3G. APOBEC3G siRNA mimicked the previously observed H19 and sulforaphane effects. In vivo, sulforaphane- or H19 or APOBEC3G siRNAs led to significantly smaller tumor xenografts with reduced expression of Ki67, APOBEC3G and phospho-Smad2. Together, we identified APOBEC3G as H19 target, and both are inhibited by sulforaphane in prevention of PDAC progression.

Silver nanoparticles (AgNPs) have attracted attention in cancer therapy and might support the treatment of pancreatic ductal adenocarcinoma (PDAC). Silver is in clinical use in wound dressings, catheters, stents and implants. However, the side effects of systemic AgNP treatment due to silver accumulation limit its therapeutic application. We evaluated whether the antioxidant and natural agent α-lipoic acid might prevent these side effects. We synthesized AgNPs using an Ionic-Pulser^® Pro silver generator and determined the concentration by inductively coupled plasma–optical emission spectrometry. The effect of α-lipoic acid was examined in four PDAC and two nonmalignant cell lines by MTT, FACS analysis, TEM, xenotransplantation and immunohistochemistry. The viability of PDAC cells was nearly totally abolished by AgNP treatment, whereas nonmalignant cells largely resisted. α-Lipoic acid prevented AgNP-induced cytotoxicity in nonmalignant cells but not in PDAC cells, which might be due to the higher sensitivity of malignant cells to silver-induced cytotoxicity. α-Lipoic acid protected mitochondria from AgNP-induced damage and led to precipitation of AgNPs. AgNPs reduced the growth of tumor xenografts, and cotreatment with α-lipoic acid protected chick embryos from AgNP-induced liver damage. Together, α-lipoic acid strongly reduced AgNP-induced side effects without weakening the therapeutic efficacy.