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: 5.33). 12/2005; 26(11):1956-64. DOI: 10.1093/carcin/bgi157
Source: PubMed


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.

    • "A number of triterpenoids are known to be promising antineoplastic agents and exhibit antiproliferative activity when tested against various cancer cell lines (Wu et al., 2010). Saleem et al. (2005) "
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    ABSTRACT: Traditional medicinal plants are often used for both the prevention and the treatment of local diseases. Taking into consideration the medicinal importance of Hedera nepalensis within local Pakistani traditions, the present study was undertaken to analyze the in vitro cancer chemopreventive and cytotoxic properties of the plant. The in vitro cancer chemopreventive testing was performed using nitrite assay, NFκB assay, aromatase assay, and quinone reductase 1 (QR1) assay. The cytotoxic potential was evaluated on three cancer-cell lines: MCF-7, MDA-MB-231, and HeLa using sulforhodamine B (SRB) assay. The results of cancer chemopreventive assays show that n-hexane and ethyl acetate fractions of tested plant have promising cancer chemopreventive potential. Lupeol isolated from n-hexane as well as ethyl acetate fraction showed lowest IC50 (0.20 ± 1.9 μM) in NFκB assay. Crude extract and its fractions inhibited the growth of three cancer cell lines by more than 60%, IC50 value of lupeol varied from 2.32 to 10.2 μM. HPLC-DAD-based quantification of lupeol in different plant tissues demonstrated that leaves of H. nepalensis are a rich source of lupeol (0.196 mg/100 mg dry weight). Our data have shown that H. nepalensis harbors cancer chemopreventive and cytotoxic agents. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Dec 2015 · Phytotherapy Research
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    • "These include its beneficial activity against inflammation, cancer, arthritis, diabetes, heart diseases, renal toxicity and hepatic toxicity [6] [7] [8] [9]. Data emanating from molecular studies with various tumorigenic models suggest that lupeol modulate host systems potentially enabling more robust antitumor responses by aberration of Ras oncoprotein and induction of Fas receptors and its adaptor protein their by inducing apoptosis [10] [11] [12] [13] [14]. "
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    ABSTRACT: There is a major unmet medical need for effective and well tolerated treatment options for cancer. The search now seeks to identify active biomolecules with multiple targets. Lupeol, a important dietary triterpenoid known as anticarcinogen by inducing apoptosis. But it is still more to reveal the potency of lupeol in the inhibition of neovascularization in cancer context. The study aimed to explore the efficacy of the lupeol in targeting angiogenesis. In this study, the inhibition of neovessel formation was assessed by preliminary antiangiogenesis assays like Chorio allontoic membrane (CAM) and rat corneal micro pocket models. Further, validated for the micro vessel density (MVD) in histological sections of peritoneum, solid tumour and xenograft tumour by immunostaing with anti CD31 antibody. Antitumour potency was verified in ascites carcinoma, solid lymphoma and human nueroblastoma xenograft in CAM. Altered angiogenic gene expression by RT-PCR, ELISA and gelatin zymography. Lupeol significantly inhibits the neovessel formation in CAM and in the rat cornea. The similar effect was ascertained in mice and human xenograft tumour models with the regressed growth. Eventually reflecting on the differential transcription of angiogenic genes like MMP-2&-9, HIF-1α, VEGFa and Flt-1 was noteworthy. It is now evident from our studies that, a new avenue of dietary triterpenoid lupeol by targeting angiogenesis, potentially inferring the multimode action in cancer prevention.
    Preview · Article · May 2014 · Biochemical and Biophysical Research Communications
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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.
    Full-text · Article · Nov 2013 · Cancer Cell International
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