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Saleem M, Kaur S, Kweon MH, Adhami VM, Afaq F, Mukhtar H. Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway

University of Wisconsin–Madison, Madison, Wisconsin, United States
Carcinogenesis (Impact Factor: 5.27). 12/2005; 26(11):1956-64. DOI: 10.1093/carcin/bgi157
Source: PubMed

ABSTRACT Pancreatic cancer is an exceptionally aggressive disease, the treatment of which has largely been unsuccessful due to higher resistance offered by pancreatic cancer cells to conventional approaches such as surgery, radiation and/or chemotherapy. The aberration of Ras oncoprotein has been linked to the induction of multiple signaling pathways and to the resistance offered by pancreatic cancer cells to apoptosis. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple pathways to induce responsiveness of pancreatic cancer cells to death signals. In this study, human pancreatic adenocarcinoma cells AsPC-1 were used to investigate the effect of Lupeol on cell growth and its effects on the modulation of multiple Ras-induced signaling pathways. Lupeol caused a dose-dependent inhibition of cell growth as assessed by MTT assay and induction of apoptosis as assessed by flow cytometry, fluorescence microscopy and western blotting. Lupeol treatment to cells was found to significantly reduce the expression of Ras oncoprotein and modulate the protein expression of various signaling molecules involved in PKCalpha/ODC, PI3K/Akt and MAPKs pathways along with a significant reduction in the activation of NFkappaB signaling pathway. Our data suggest that Lupeol can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of pancreatic cancer cells. Lupeol could be a potential agent against pancreatic cancer, however, further in-depth in vivo studies are warranted.

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    • "Extensive research over the last three decades has revealed various important pharmacological activities of lupeol under in vitro and in vivo conditions, including anti-inflammation, anti-arthritis, anti-diabetes, anti-heart diseases, anti-renal toxicity, anti-hepatic toxicity and anti-cancer [13-15]. Lupeol has been reported not only to induce differentiation and inhibit the growth of melanoma and leukemia cells [16-19], but also to inhibit tumor promotion in two-stage mouse skin carcinogenesis through modulating NF-κB and PI3-kinase (PI3K)/Akt pathways [20], and to inhibit growth and induce apoptosis in both prostate [21] and pancreatic cancers [22]. Recent studies have also shown that lupeol induced apoptosis of HCC cells SMMC7721 by down-regulating death receptor 3 (DR3) [23], and also had in vivo and in vitro therapeutic effect for HCC by targeting liver tumor-initiating cells (T-ICs) through modulating PTEN-Akt-ABCG2 pathway [24]. "
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    ABSTRACT: Background Lup-20(29)-en-3H-ol (Lupeol), a dietary triterpene, has been shown to possess multiple pharmacological activities including anti-tumor effects Methods In the current study, we noted that low doses of lupeol (<40 μM) promoted the growth of hepatocellular carcinoma (HCC) cells with a significant activation of the PI3-kinase/Akt signaling pathway. We further investigated the combined anti-tumor effect of lupeol and S14161, a newly identified PI3-Kinase inhibitor in vitro and in vivo Results The results demonstrated that lupeol and S14161 could exert a synergistic antitumor effect resulting in chemo-sensitization of HCC to low doses of lupeol. Using an in vivo HCC model, we further demonstrated that lupeol and S14161 synergistically inhibited tumor growth without any adverse effects on body weight Conclusion Our studies showed that the activation of PI3-kinase/Akt pathway resulted in the tumor-promoting effect with low doses of lupeol. Combining PI3-kinase inhibitor with lupeol could synergistically augment the anti-tumor effect of lupeol and might be an applicable strategy for HCC therapy.
    Cancer Cell International 11/2013; 13(1):108. DOI:10.1186/1475-2867-13-108 · 1.99 Impact Factor
    • "The antiinflammatory potential of Lupeol in a mouse model of arthritis and bronchial asthma also has been shown [235] [236]. Therefore, antitumor properties of lupeol were investigated in various cancers and it was found to inhibit ovarian [237], breast [238], pancreatic [239] [240], colon [241], stomach, renal, fibrosarcoma, and bladder cancer [239]. Taken together, the evidence argues strongly that the therapeutic usefulness of Lupeol for inflammatory conditions and cancer warrants further investigation. "
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    ABSTRACT: Every year more than a million new cancer cases and 600,000 deaths are reported world-wide. Colorectal cancer is the fourth most commonly occurring and second leading cause of cancer deaths in the United States. Significant progress has been made in understanding colorectal cancer through epidemiological, laboratory and clinical studies. Development of metastatic adenocarcinomas is a multistage process occurring over several years during which multiple genetic alterations and pathophysiological changes are associated. Colorectal cancer can be prevented if the transformation of normal colonic crypt cells to malignant can be halted or reversed. Some of the key molecules that are altered significantly and play important roles in colorectal tumor progression are associated with inflammation. Since chronic inflammation is now recognized as a potential risk factor for tumor development, targeting inflammatory pathways has proven effective in preventing formation of colonic tumors and their malignant progression in both preclinical and clinical studies. Synthetic non-steroidal anti-inflammatory drugs (NSAIDS) have been identified as potential colorectal cancer chemopreventive agents; however, most of these synthetic agents are associated with unwanted and sometimes fatal side effects. There is mounting evidence in support of the efficacy of naturally-occurring phytochemicals possessing anti-inflammatory activity. In this review we discuss key inflammatory pathways associated with colorectal cancer and promising naturally-occurring phytochemicals as anti-inflammatory agents for the prevention and treatment of colorectal cancer.
    Current cancer drug targets 04/2013; 13(5). DOI:10.2174/15680096113139990036 · 3.58 Impact Factor
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    • "Therefore, the authors, taking advantage of animal modelling and immune gene therapy, suggest a novel strategy in pancreatic cancer treatment. As IL-25 binding to its receptor leads to apoptosis of cancerous cells, it can also be used to treat pancreatic cancer [39], because one of the main causes of pancreatic cancer is resistance to apoptosis [40]. "
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    ABSTRACT: Pancreatic cancer is an aggressive type of malignancy. Generally, its promotion and progression are due to the disturbance in some cellular and molecular mechanisms, particularly deregulation of programmed cell death or apoptosis. Certainly, loss of counterbalance between generation and cell death will lead to the tumoural mass development in various tissues, such as pancreas.From earlier decades, a variety of treatments as chemotherapy, radiation and surgery have been employed in order to pancreatic cancer remedial purposes, which are associated with infirm medical outcome. Therefore, with regard to the anti-cancerous and pro-apoptotic properties of the cytokine interleukin-25 (IL-25), the authors intend to anticipate a new therapeutic strategy. IL-25 – known as IL-17E – is one of the major factors responsible for death receptor-mediated pathway. Broadly, its receptor is located on multifarious cells such as pancreatic cancerous cells. We proposed to select four groups of C57BL/6 mice, for IL-25 gene inoculation, via mesenchymal stem cells as a vector, in order to increase exposure of cancerous cells to IL-25. IL-25 could activate apoptotic mediators including tumour necrosis factor receptor associated factor (TRAF6), Fas-Associated protein with Death Domain (FADD) and caspases consequently. Probably this method will be efficient in pancreatic malignancy treatment, via inducing apoptosis in pancreatic tumoural cells.
    Iranian Journal of Medical Hypotheses and Ideas 07/2012; 6(2):75–79. DOI:10.1016/j.jmhi.2012.08.003
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