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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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Related in: MedlinePlus

Plasma levels of NF-κB regulated inflammatory cytokines. Mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system to determine the concentration of 23 different cytokines and growth factors. The levels of A) IL-1α, B) IL-1β, C) IL-12p40, D) IL-17, E) MCP-1, F) TNF-α, G) Eotaxin, and H) MIP-1β in placebo (P, n = 8), DMAPT (n = 12), gemcitabine (Gem, n = 10) and DMAPT/gemcitabine (DM/Gem, n = 9) groups are shown. The means are indicated by the horizontal lines. * P < 0.05 vs. placebo.
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Figure 7: Plasma levels of NF-κB regulated inflammatory cytokines. Mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system to determine the concentration of 23 different cytokines and growth factors. The levels of A) IL-1α, B) IL-1β, C) IL-12p40, D) IL-17, E) MCP-1, F) TNF-α, G) Eotaxin, and H) MIP-1β in placebo (P, n = 8), DMAPT (n = 12), gemcitabine (Gem, n = 10) and DMAPT/gemcitabine (DM/Gem, n = 9) groups are shown. The means are indicated by the horizontal lines. * P < 0.05 vs. placebo.

Mentions: To identify possible indicators or mediators of drug response, mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system that can simultaneously detect the level of 23 different cytokines and growth factors (interleukin [IL]-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12[p40], IL-12[p70], IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony stimulating factor [GM-CSF], interferon-gamma [IFN-γ], interleukin-8 homologue KC, monocyte chemotactic protein-1 [MCP-1, MCAF], macrophage inflammatory protein-1 alpha [MIP-1α], MIP-1β, RANTES, and tumor necrosis factor-alpha [TNF-α]). Gemcitabine significantly increased the plasma levels of IL-1α, IL-1β, and IL-17 compared to placebo (Figures 7A, B & D); DMAPT/gemcitabine treatment reduced these cytokine levels back to the placebo levels. DMAPT and DMAPT/gemcitabine significantly decreased the levels of IL-12p40, MCP-1 and TNF-α relative to placebo (Figures 7C, E & F). Although DMAPT and DMAPT/gemcitabine also reduced the levels of eotaxin and MIP-1β, the decreases were only significant for the combination (Figures 7G & H). Importantly, these eight cytokines are proinflammatory cytokines and known NF-κB target genes. Taken together, these results suggest that gemcitabine induces the expression of several pro-inflammatory NF-κB regulated cytokine genes. In contrast, treatment with DMAPT or the combination reduces the plasma levels of pro-inflammatory NF-κB-regulated cytokines, demonstrating NF-κB suppression by DMAPT.


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)

Plasma levels of NF-κB regulated inflammatory cytokines. Mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system to determine the concentration of 23 different cytokines and growth factors. The levels of A) IL-1α, B) IL-1β, C) IL-12p40, D) IL-17, E) MCP-1, F) TNF-α, G) Eotaxin, and H) MIP-1β in placebo (P, n = 8), DMAPT (n = 12), gemcitabine (Gem, n = 10) and DMAPT/gemcitabine (DM/Gem, n = 9) groups are shown. The means are indicated by the horizontal lines. * P < 0.05 vs. placebo.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Plasma levels of NF-κB regulated inflammatory cytokines. Mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system to determine the concentration of 23 different cytokines and growth factors. The levels of A) IL-1α, B) IL-1β, C) IL-12p40, D) IL-17, E) MCP-1, F) TNF-α, G) Eotaxin, and H) MIP-1β in placebo (P, n = 8), DMAPT (n = 12), gemcitabine (Gem, n = 10) and DMAPT/gemcitabine (DM/Gem, n = 9) groups are shown. The means are indicated by the horizontal lines. * P < 0.05 vs. placebo.
Mentions: To identify possible indicators or mediators of drug response, mouse plasma obtained at the time of sacrifice was analyzed using the Bio-Plex 200 system that can simultaneously detect the level of 23 different cytokines and growth factors (interleukin [IL]-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12[p40], IL-12[p70], IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony stimulating factor [GM-CSF], interferon-gamma [IFN-γ], interleukin-8 homologue KC, monocyte chemotactic protein-1 [MCP-1, MCAF], macrophage inflammatory protein-1 alpha [MIP-1α], MIP-1β, RANTES, and tumor necrosis factor-alpha [TNF-α]). Gemcitabine significantly increased the plasma levels of IL-1α, IL-1β, and IL-17 compared to placebo (Figures 7A, B & D); DMAPT/gemcitabine treatment reduced these cytokine levels back to the placebo levels. DMAPT and DMAPT/gemcitabine significantly decreased the levels of IL-12p40, MCP-1 and TNF-α relative to placebo (Figures 7C, E & F). Although DMAPT and DMAPT/gemcitabine also reduced the levels of eotaxin and MIP-1β, the decreases were only significant for the combination (Figures 7G & H). Importantly, these eight cytokines are proinflammatory cytokines and known NF-κB target genes. Taken together, these results suggest that gemcitabine induces the expression of several pro-inflammatory NF-κB regulated cytokine genes. In contrast, treatment with DMAPT or the combination reduces the plasma levels of pro-inflammatory NF-κB-regulated cytokines, demonstrating NF-κB suppression by DMAPT.

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