Prolonged survival and delayed progression of pancreatic intraepithelial neoplasia in LSL-KrasG12D/+;Pdx-1-Cre mice by vitamin E -tocotrienol

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Carcinogenesis (Impact Factor: 5.33). 01/2013; 34(4). DOI: 10.1093/carcin/bgt002
Source: PubMed


The highly lethal nature of pancreatic cancer and the increasing recognition of high-risk individuals have made research into chemoprevention a high priority. Here, we tested the chemopreventive activity of δ-tocotrienol, a bioactive vitamin E derivative extracted from palm fruit, in the LSL-KrasG12D/+;Pdx-1-Cre pancreatic cancer mouse model. At 10 weeks of age, mice (n = 92) were randomly allocated to three groups: 1) no treatment, 2) vehicle, and 3) δ-tocotrienol (200 mg/kg x 2/day, PO). Treatment was continued for 12 months. Mice treated with δ-tocotrienol showed increased median survival from the onset of treatment (11.1 months) compared to vehicle-treated mice (9.7 months) and non-treated mice (8.5 months) (P<0.025). Importantly, none of the mice treated with δ-tocotrienol harbored invasive cancer compared with 10% and 8% in vehicle-treated and non-treated mice, respectively. Furthermore, δ-tocotrienol treatment also resulted in significant suppression of mouse pancreatic intraepithelial neoplasm (mPanIN) progression compared to vehicle-treated and non-treated mice: mPanIN-1: 47-50% (P<0.09), mPanIN-2: 6-11% (P<0.001), mPanIN-3: 3-15% (P<0.001), and invasive cancer: 0-10% (P<0.001). δ-Tocotrienol treatment inhibited mutant Kras-driven pathways such as MEK/ERK, PI3K/AKT, and NF-kB/p65, as well as Bcl-xL and induced p27. δ-Tocotrienol also induced biomarkers of apoptosis such as Bax and activated caspase 3 along with an increase in plasma levels of CK18. In summary, δ-tocotrienol's ability to interfere with oncogenic Kras pathways coupled with the observed increase in median survival and significant delay in PanIN progression highlight the chemopreventative potential of δ-tocotrienol and warrant further investigation of this micronutrient in individuals at high risk for pancreatic cancer.

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    • "Furthermore, genetic variations in antioxidant genes seem to modify the risk to develop PDAC in humans (Tang et al., 2010). In line, long-term treatment with δ-tocotrienol (a bioactive vitamin E derivative) which has putative anti-oxidative activity dramatically inhibited KrasG12D-driven formation of pancreatic intraepithelial neoplasms (mPanINs) in a genetically engineered mouse model (GEMM) of pancreatic cancer (Husain et al., 2011, 2013; Shin-Kang et al., 2011). These data suggest that a systemic reduction in the production of reactive oxygen species (ROS) may prevent/delay the development of PDAC. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease without clearly known disease causes. Recent epidemiological and animal studies suggest that the supplementation of dietary antioxidants (e.g., vitamins C and E) decreases cancer risk, implying that increased reactive oxygen species (ROS) may play a role in pancreatic carcinogenesis. However, oncogenic Kras mutations (e.g., Kras(G12D)), which are present in more than 90% of PDAC, have been proven to foster low intracellular ROS levels. Here, oncogenic Kras activates expression of a series of anti-oxidant genes via Nrf2 (nuclear factor, erythroid derived 2, like 2) and also mediates an unusual metabolic pathway of glutamine to generate NADPH. This can then be used as the reducing power for ROS detoxification, leading collectively to low ROS levels in pancreatic pre-neoplastic cells and in cancer cells. In adult stem cells and cancer stem cells, low ROS levels have been associated with the formation of a proliferation-permissive intracellular environment and with perseverance of self-renewal capacities. Therefore, it is conceivable that low intracellular ROS levels may contribute significantly to oncogenic Kras-mediated PDAC formation.
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    ABSTRACT: Previous work has shown that vitamin E δ-tocotrienol (VEDT) prolongs survival and delays progression of pancreatic cancer in the LSL-KrasG12D/+;Pdx-1-Cre mouse model of pancreatic cancer. However, the effect of VEDT alone or in combination with gemcitabine in the more aggressive LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is unknown. Here, we studied the effects of VEDT and the combination of VEDT and gemcitabine in the KPC mice. KPC mice were randomized into 4 groups: 1) vehicle (olive oil, 1.0 mL/kg PO twice/day and PBS 1.0 mL/kg IP twice/week), 2) gemcitabine (100 mg/kg IP twice/week), 3) VEDT (200 mg/kg PO twice/day), and 4) gemcitabine + VEDT. Mice received treatment until they displayed symptoms of impending death from pancreatic cancer, at which point animals were euthanized. At 16 weeks, survival was 10% in the vehicle group, 30% in the gemcitabine group, 70% in the VEDT group (P<0.01), and 90% in the VEDT combined with gemcitabine group (P<0.05). VEDT alone and combined with gemcitabine resulted in reversal of epithelial-to-mesenchymal transition in tumors. Biomarkers of apoptosis (plasma CK18), PARP1 cleavage, and Bax expression were more greatly induced in tumors subjected to combined treatment versus individual treatment. Combined treatment induced cell cycle inhibitors (p27Kip1 and p21Cip1) and inhibited VEGF, vascularity (CD31), and oncogenic signaling (pAKT, pMEK, and pERK) greater than individual drugs. No significant differences in body weight gain between drug treatment and control mice were observed. These results strongly support further investigation of VEDT alone and in combination with gemcitabine for pancreatic cancer prevention and treatment.
    Preview · Article · Aug 2013 · Cancer Prevention Research
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