BACKGROUND: Since for pancreatic cancer the mortality rate approaches the incidence rate with only 1-4% of all patients surviving 5 years, it would be would be of great value to provide chemopreventive treatment for high-risk individuals. DISCUSSION: The preclinical study of pancreatic intraepithelial neoplasia (PanINs) has recently been made possible by the generation of genetically modified animal models, which recapitulate human PanINs and invasive pancreatic cancer on a genetic and histomorphologic level. Very recently, several groups have reported first evidence of chemoprevention of pancreatic cancer.
"Early diagnosis of this disease is difficult because it develops without any early symptoms. Survival of patients with pancreatic cancer has been <5% over 5 years which makes this disease of great concern (2). Therapeutic outcomes with pancreatic cancer are not useful for patients especially upon a late diagnosis thus strategies to prevent this disease from occurring have become an important area of research. "
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is the fourth largest cause of cancer deaths in the Unites States and the prognosis is grim with <5% survival chances upon diagnosis. The objective of this study was to assess the combined chemopreventive effect of solid lipid nanoparticle (SLN) encapsulated drugs aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN) for the chemoprevention of pancreatic cancer. Experiments were carried out (1) to evaluate the feasibility of encapsulation of these chemopreventive agents within solid lipid systems and (2) to measure the synergistic effects of a combination of ASP with CUR in SLNs mixed with free SFN against cell proliferation and apoptosis in pancreatic cancer cells, MIA PaCa-2 and Panc-1. The SLNs were prepared using a modified solvent evaporation technique and were characterized for particle sizing, encapsulation efficiency and drug release. ASP and CUR SLNs were formulated within the particle size range of 150‑250 nm and were found to have an encapsulation efficiency of 85 and 69%, respectively. Sustained release of drugs over a 96 h period from SLNs was observed. The SLNs were stable over a 3-month storage period at room temperature. Cell viability studies demonstrated that combinations of low doses of ASP SLN (25 µM), CUR SLN (2.5 µM) and free SFN (5 µM) significantly reduced cell viability by 43.6 and 48.49% in MIAPaca-2 and Panc-1 cell lines, respectively. Furthermore, increased apoptosis of 61.3 and 60.37% was found in MIA Paca-2 and Panc-1 cell lines, respectively, in comparison to the individual doses administered. Synergistic effects were demonstrated using MTS and apoptosis assays. Thus, this study successfully demonstrated the feasibility of using a solid lipid nanoparticulate system for the first time to deliver this novel combination chemoprevention regimen, providing valuable evidence for the usability of nanotechnology-based drug regimens towards pancreatic cancer chemoprevention.
International Journal of Oncology 01/2013; 41(6):2260. DOI:10.3892/ijo.2012.1636 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is among the most dismal of human malignancies. There are no chemopreventive strategies for pancreatic cancer or its precursor lesions, pancreatic intraepithelial neoplasia (PanINs). Recent evidence suggests that statins have potential chemopreventive abilities. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of this drug.
Simvastatin was injected i.p. in LsL-Kras(G12D); Pdx1-Cre or LsL-Kras(G12D);LsL-Trp53(R172H);Pdx1-Cre mice. After five months, animals were sacrificed. The effect of simvastatin was evaluated by histopathological analyses, immunostaining, and real-time PCR.
After five months of treatment, simvastatin was able to significantly delay progression of mPanINs in LsL-Kras(G12D); Pdx1-Cre mice. Furthermore, formation of invasive pancreatic cancer in LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre transgenic mice was partially inhibited by simvastatin. Invasive murine pancreatic cancer was identified in 9 of 12 (75%) LsL-Kras(G12D); LsL-Trp53(R172H);Pdx1-Cre untreated control mice. In contrast, transgenic mice treated with Simvastatin, only 4 out of 10 (40%, p = 0.004) developed murine pancreatic cancer during the study. Using real-time PCR we found a significant up-regulation of Hmgcr as sign of blocking HMG-CoA reductase, a key enzyme in the cholesterol biosynthesis. This shows our ability to achieve effective pharmacologic levels of simvastatin during pancreatic cancer formation in vivo.
Using a transgenic mouse model that recapitulates human pancreatic cancer, this study provides first evidence that simvastatin is an effective chemopreventive agent by delaying the progression of PanINs and partially inhibit the formation of murine pancreatic cancer.
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