Dimethylaminoparthenolide and gemcitabine: a survival study using a genetically engineered mouse model of pancreatic cancer

Abstract

BackgroundPancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-κB) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-κB activation may result in chemoresistance. We hypothesize that NF-κB suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer.MethodsThe efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett’s post-test, Student’s t-test, and Fisher exact test.ResultsGemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were observed, suggesting prevention of higher grade lesions in these animals. While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1α (IL-1α), IL-1β, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), eotaxin, and tumor necrosis factor-alpha (TNF-α), all of which are NF-κB target genes.ConclusionIn summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

A 3D bioinspired highly porous polymeric scaffolding system forin vitrosimulation of pancreatic ductal adenocarcinoma

“…92 Furthermore, the secretion of collagen-I was monitored, as collagen-I is an important feature of PDAC microenvironment which is highly secreted within the densely-packed pancreatic tumour stroma, as proven by patient and animal studies. 76,93,94 We observed a signicant collagen-I secretion in the FN coated scaffolds (Fig. 6a, c and 7) and no collagen-I secretion in uncoated scaffolds (Fig.…”

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

“…Once the tumor became palpable, mice were randomized according to tumor size and gemcitabine treatment was started. The mice were injected with gemcitabine (50 mg/kg in PBS) or vehicle (PBS) intraperitoneally twice per week and the tumor growth and body weight were measured for 21 days (36,37). Tumor growth and relative tumor volume (RTV) were measured as per our established method (33) using studylog R measurement tools and software (California) three times a week.…”

Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells

“…Meanwhile, DMAPT combined with gemcitabine remarkably decreases tumor size and the incidence of the metastasis to liver in mouse models of pancreatic cancer [16]. However, there is no generally accepted molecular target with regard to the anti-tumor activity of DMAPT up to date.…”