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

Yip-Schneider MT, Wu H, Stantz K, Agaram N, Crooks PA, Schmidt CM - BMC Cancer (2013)

Bottom Line: Gemcitabine 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St,, Building R3, Rm. 541C, Indianapolis, IN 46202, USA. myipschn@iupui.edu

ABSTRACT

Background: Pancreatic 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.

Methods: The 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.

Results: Gemcitabine 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.

Conclusion: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

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Pancreas histology and expression of NF-κB and P-ERK. A) H&E. Representative sections of normal adjacent pancreas upon sacrifice at day 219 [d219]), mPanIN-1 (asterisk) and −2 (black arrowhead) at d271, and pancreatic ductal adenocarcinoma at d258 are shown (200X magnification). B) NF-κB. Pancreatic tissue sections were immunostained with a NF-κB specific antibody. Representative images of normal adjacent pancreas at d231, mPanIN-1 (asterisk) and −2 (black arrowhead) at d226, and adenocarcinoma at d239 are shown (200X magnification). NF-κB is expressed in mPanINs and tumor cells (brown). C) P-ERK. Positive P-ERK staining (brown) was localized to the mPanINs (d226) and tumor cells (d295) but was absent in normal adjacent pancreas (d226) (200X magnification).
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Figure 3: Pancreas histology and expression of NF-κB and P-ERK. A) H&E. Representative sections of normal adjacent pancreas upon sacrifice at day 219 [d219]), mPanIN-1 (asterisk) and −2 (black arrowhead) at d271, and pancreatic ductal adenocarcinoma at d258 are shown (200X magnification). B) NF-κB. Pancreatic tissue sections were immunostained with a NF-κB specific antibody. Representative images of normal adjacent pancreas at d231, mPanIN-1 (asterisk) and −2 (black arrowhead) at d226, and adenocarcinoma at d239 are shown (200X magnification). NF-κB is expressed in mPanINs and tumor cells (brown). C) P-ERK. Positive P-ERK staining (brown) was localized to the mPanINs (d226) and tumor cells (d295) but was absent in normal adjacent pancreas (d226) (200X magnification).

Mentions: Premalignant lesions, known as pancreatic intraepithelial neoplasia (PanINs), arise in the pancreas and are precursors to invasive pancreatic ductal adenocarcinoma [32]. All stages of mouse PanINs (mPanINs) and pancreatic adenocarcinoma, mirroring those observed in humans, are represented in the LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice (Figure 3A). The percentages of normal pancreatic ducts and mPanIN-1, -2 and −3 were quantified for each of the treatment groups; however, no significant differences were observed (Figure 4A). Few mPanINs were present in pancreata bearing large tumors. In addition, pancreata in which no tumors formed were separately analyzed to determine the extent of pre-neoplasia (Figure 4B); no significant differences in the % normal ducts or pancreatic lesions were observed between the three drug treatment groups. Interestingly, mostly normal ducts or low grade PanIN-1 lesions were observed in these pancreata, suggesting that not only tumor formation but also the development of higher grade pancreatic lesions is prevented in these animals. This was also confirmed by the incidence of PanIN-2 and −3 lesions in pancreata lacking tumors (Figure 4B, table), with the lowest incidence in the DMAPT/Gem treatment group (17%).


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

Yip-Schneider MT, Wu H, Stantz K, Agaram N, Crooks PA, Schmidt CM - BMC Cancer (2013)

Pancreas histology and expression of NF-κB and P-ERK. A) H&E. Representative sections of normal adjacent pancreas upon sacrifice at day 219 [d219]), mPanIN-1 (asterisk) and −2 (black arrowhead) at d271, and pancreatic ductal adenocarcinoma at d258 are shown (200X magnification). B) NF-κB. Pancreatic tissue sections were immunostained with a NF-κB specific antibody. Representative images of normal adjacent pancreas at d231, mPanIN-1 (asterisk) and −2 (black arrowhead) at d226, and adenocarcinoma at d239 are shown (200X magnification). NF-κB is expressed in mPanINs and tumor cells (brown). C) P-ERK. Positive P-ERK staining (brown) was localized to the mPanINs (d226) and tumor cells (d295) but was absent in normal adjacent pancreas (d226) (200X magnification).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672012&req=5

Figure 3: Pancreas histology and expression of NF-κB and P-ERK. A) H&E. Representative sections of normal adjacent pancreas upon sacrifice at day 219 [d219]), mPanIN-1 (asterisk) and −2 (black arrowhead) at d271, and pancreatic ductal adenocarcinoma at d258 are shown (200X magnification). B) NF-κB. Pancreatic tissue sections were immunostained with a NF-κB specific antibody. Representative images of normal adjacent pancreas at d231, mPanIN-1 (asterisk) and −2 (black arrowhead) at d226, and adenocarcinoma at d239 are shown (200X magnification). NF-κB is expressed in mPanINs and tumor cells (brown). C) P-ERK. Positive P-ERK staining (brown) was localized to the mPanINs (d226) and tumor cells (d295) but was absent in normal adjacent pancreas (d226) (200X magnification).
Mentions: Premalignant lesions, known as pancreatic intraepithelial neoplasia (PanINs), arise in the pancreas and are precursors to invasive pancreatic ductal adenocarcinoma [32]. All stages of mouse PanINs (mPanINs) and pancreatic adenocarcinoma, mirroring those observed in humans, are represented in the LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mice (Figure 3A). The percentages of normal pancreatic ducts and mPanIN-1, -2 and −3 were quantified for each of the treatment groups; however, no significant differences were observed (Figure 4A). Few mPanINs were present in pancreata bearing large tumors. In addition, pancreata in which no tumors formed were separately analyzed to determine the extent of pre-neoplasia (Figure 4B); no significant differences in the % normal ducts or pancreatic lesions were observed between the three drug treatment groups. Interestingly, mostly normal ducts or low grade PanIN-1 lesions were observed in these pancreata, suggesting that not only tumor formation but also the development of higher grade pancreatic lesions is prevented in these animals. This was also confirmed by the incidence of PanIN-2 and −3 lesions in pancreata lacking tumors (Figure 4B, table), with the lowest incidence in the DMAPT/Gem treatment group (17%).

Bottom Line: Gemcitabine 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St,, Building R3, Rm. 541C, Indianapolis, IN 46202, USA. myipschn@iupui.edu

ABSTRACT

Background: Pancreatic 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.

Methods: The 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.

Results: Gemcitabine 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.

Conclusion: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

Show MeSH
Related in: MedlinePlus