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Mohammad Saleem - One of the best experts on this subject based on the ideXlab platform.
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Lupeol a novel androgen receptor inhibitor implications in prostate cancer therapy
Clinical Cancer Research, 2011Co-Authors: Hifzur R Siddique, Shrawan K Mishra, Jeffery R Karnes, Mohammad SaleemAbstract:Purpose: Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration-resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify those agents that could target AR for both disease types. We provide mechanism-based evidence that Lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of androgen receptor (AR) in vitro and in vivo . Experimental Design: Normal prostate epithelial cell (RWPE-1), LAPC4 (wild functional AR/ADPC), LNCaP (mutant functional/AR/ADPC), and C4-2b (mutant functional/AR/CRPC) cells were used to test the anti-AR activity of Lupeol. Cells grown under androgen-rich environment and treated with Lupeol were tested for proliferation, AR transcriptional activity, AR competitive ligand binding, AR–DNA binding, and AR–ARE/target gene binding. Furthermore, in silico molecular modeling for Lupeol–AR binding was done. Athymic mice bearing C4-2b and LNCaP cell–originated tumors were treated intraperitoneally with Lupeol (40 mg/kg; 3 times/wk) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, Lupeol serum levels were measured. Results: Lupeol significantly inhibited R1881 (androgen analogue) induced (i) transcriptional activity of AR and (ii) expression of PSA. Lupeol (i) competed antagonistically with androgen for AR, (ii) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK, and IL-6, and (iii) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to antihormone therapy. High-performance liquid chromatography analysis showed that Lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels. Conclusion: Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP. Clin Cancer Res; 17(16); 5379–91. ©2011 AACR .
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beneficial health effects of Lupeol triterpene a review of preclinical studies
Life Sciences, 2011Co-Authors: Hifzur R Siddique, Mohammad SaleemAbstract:Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of Lupeol. Various in vitro and preclinical animal studies suggest that Lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, Lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that Lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that Lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, ILβ, proteases, α-glucosidase, cFLIP, Bcl-2 and NFκB. This minireview discusses in detail the preclinical studies conducted with Lupeol and provides an insight into its mechanisms of action.
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Lupeol triterpene a novel diet based microtubule targeting agent disrupts survivin cflip activation in prostate cancer cells
Biochemical and Biophysical Research Communications, 2009Co-Authors: Mohammad Saleem, Imtiyaz Murtaza, Olya Witkowsky, Amanda M Kohl, Nityanand MaddodiAbstract:Abstract Recently we showed Lupeol, a triterpene, found in fruits and vegetables inhibits the growth of tumors originated from human androgen-sensitive prostate cancer (CaP) cells and decreases the serum-PSA levels in a mouse model. Here, we provide evidence that Lupeol inhibits the growth of androgen-sensitive as well as androgen-insensitive CaP cells by inducing G2/M cell cycle arrest without exhibiting any toxicity to normal human prostate epithelial cells (PrEC) at the doses at which it kills cancer cells. We observed that Lupeol treatment to LNCaP and DU145 cells resulted in a dose-dependent (i) decrease in the protein levels of Cyclins-A, -B1, -D1, -D2, -E2, cyclin-dependent kinase (cdk)-2 and (ii) increase in the protein level of CDK-inhibitor p21. Since G2/M cell cycle phase is regulated by microtubule assembly, we investigated effect of Lupeol on microtubule assembly, its regulation and down-stream targets in CaP cells. Lupeol treatment significantly modulated the level of (i) microtubule components α-tubulin and β-tubulin, (ii) microtubule-regulatory protein stathmin, and (iii) microtubule-regulatory down-stream target/pro-survival protein survivin. Lupeol treatment also decreased the level of anti-apoptotic protein cFLIP. Finally, Lupeol was observed to significantly decrease the transcriptional activation of survivin and cFLIP genes in CaP cells. We conclude that the Lupeol-induced growth inhibition of CaP cells is a net outcome of simultaneous effects on stathmin, cFLIP, and survivin which results in the disruption of microtubule assembly. We suggest that Lupeol alone or as an adjuvant to other microtubule agents could be developed as a potential agent for the treatment of human CaP.
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Lupeol inhibits proliferation of human prostate cancer cells by targeting β catenin signaling
Carcinogenesis, 2009Co-Authors: Mohammad Saleem, Imtiyaz Murtaza, Vaqar M Adhami, Naghma Khan, Mohammad Asim, Yewseok Suh, Rohinton Tarapore, Jeremy J Johnson, Imtiaz A Siddiqui, Bilal Bin HafeezAbstract:Lupeol, a dietary triterpene, was shown to decrease serum prostate-specific antigen levels and inhibit the tumorigenicity of prostate cancer (CaP) cells in vivo. Here, we show that Lupeol inhibits the proliferative potential of CaP cells and delineated its mechanism of action. Employing a focused microarray of human CaP-associated genes, we found that Lupeol significantly modulates the expression level of genes such as ERBB2, tissue inhibitor of metalloproteinases-3, cyclin D1 and matrix metalloproteinase (MMP)-2 that are known to be associated with proliferation and survival. A common feature of these genes is that all of them are known to either regulate or act as downstream target of β-catenin signaling that is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of β-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of glycogen synthase kinase 3 beta (GSK3β)–axin complex (regulator of β-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of β-catenin), (4) reduced the transcriptional activation of T Cell Factor (TCF) responsive element (marker for β-catenin signaling) in pTK-TCF-Luc-transfected cells and (5) decreased the transcriptional activation of MMP-2 gene in pGL2-MMP-2-Luc-transfected cells. Effects of Lupeol treatment on β-catenin degradation were significantly reduced in CaP cells where axin is knocked down through small interfering RNA transfection and GSK3β activity is blocked. Collectively, these data suggest the multitarget efficacy of Lupeol on β-catenin-signaling network thus resulting in the inhibition CaP cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human CaP.
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suppression of cflip by Lupeol a dietary triterpene is sufficient to overcome resistance to trail mediated apoptosis in chemoresistant human pancreatic cancer cells
Cancer Research, 2009Co-Authors: Imtiyaz Murtaza, Mohammad Saleem, Vaqar M Adhami, Bilal Bin Hafeez, Hasan MukhtarAbstract:Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of Lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy-resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of Lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of Lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with Lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, Lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of Lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that Lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC.
Hasan Mukhtar - One of the best experts on this subject based on the ideXlab platform.
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the dietary terpene Lupeol targets colorectal cancer cells with constitutively active wnt β catenin signaling
Molecular Nutrition & Food Research, 2013Co-Authors: Rohinton Tarapore, Vaqar M Adhami, Imtiaz A Siddiqui, Vladimir S Spiegelman, Hasan MukhtarAbstract:Scope Aberrant activation of the Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin signaling pathway is the most common modification, and often considered, a hallmark of colorectal cancer (CRC). Typically in this pathway the β-catenin translocates from the cytoplasm to the nucleus, where it functions as a transcription regulator of several genes that support tumor formation and progression. Thus, any agent that could attenuate the translocation of β-catenin could be extremely valuable against CRC, especially the tumors that exhibit constitutively active Wnt/β-catenin signaling. Methods and results Using human CRC cells that exhibit differential expression of Wnt/β-catenin signaling, we demonstrate that treatment of CRC cells with dietary triterpene Lupeol results in a dose-dependent (i) decrease in cell viability, (ii) induction of apoptosis, (iii) decrease in colonogenic potential, (iv) decrease in β-catenin transcriptional activity, and (v) decrease in the expression of Wnt target genes. Most importantly Lupeol was observed to inhibit the translocation of β-catenin from the cytoplasm to the nucleus. Importantly, all these effects of Lupeol were restricted to cells that harbor constitutively active Wnt/β-catenin signaling while negligible effects were observed in cells that lack constitutively active Wnt/β-catenin signaling. Further, we also demonstrate that inhibition of Wnt signaling in cells with constitutive active Wnt/β-catenin results in loss of Lupeol efficacy while inducing Wnt signaling sensitizes the cells to inhibitory effects of Lupeol. Conclusion In summary, our data strongly advocate the efficacy of Lupeol against CRC cells that exhibit constitutively active Wnt/β-catenin signaling.
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suppression of cflip by Lupeol a dietary triterpene is sufficient to overcome resistance to trail mediated apoptosis in chemoresistant human pancreatic cancer cells
Cancer Research, 2009Co-Authors: Imtiyaz Murtaza, Mohammad Saleem, Vaqar M Adhami, Bilal Bin Hafeez, Hasan MukhtarAbstract:Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of Lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy-resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of Lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of Lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with Lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, Lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of Lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that Lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC.
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Lupeol inhibits growth of highly aggressive human metastatic melanoma cells in vitro and in vivo by inducing apoptosis
Clinical Cancer Research, 2008Co-Authors: Mohammad Saleem, Bilal Bin Hafeez, Nityanand Maddodi, Mohammad Abu Zaid, Naghma Khan, Mohammad Asim, Yewseok Suh, Jungmi Yun, Vijayasaradhi Setaluri, Hasan MukhtarAbstract:Purpose: Poor prognosis of metastatic melanoma mandates the development of novel strategies for its treatment and prevention. In this study, the effect of Lupeol, a diet-based triterpene, was determined on the growth and tumorigenicity of human melanoma cells in vitro and in vivo . Experimental Design: Normal human melanocytes, and human metastatic (451Lu) and nonmetastatic (WM35) cells were treated with Lupeol; its effect on growth, proliferation, and apoptosis were evaluated. Further athymic nude mice bearing 451Lu cell–originated tumors were administered with Lupeol thrice a week, and its effect on tumor growth and surrogate biomarkers was evaluated. Results: Lupeol significantly decreased the viability of 451Lu and WM35 melanoma cells but had only a marginal effect on normal human melanocyte cells at similar doses. Lupeol treatment of 451Lu cells caused ( a ) G 1 -S phase cell cycle arrest and apoptosis; ( b ) down-regulation of Bcl2 and up-regulation of Bax; ( c ) activation of caspase-3 and induction of poly(ADP)ribose polymerase cleavage; ( d ) decreased expression of cyclin D1, cyclin D2, and cdk2; and ( e ) increased expression of p21 protein. Next, Lupeol significantly reduced 451Lu tumor growth in athymic nude mice and modulated the expression of proliferation markers, apoptotic markers, and cell cycle regulatory molecules in tumor xenografts. Conclusion: Our findings showed the anticancer efficacy of Lupeol with mechanistic rationale against metastatic human melanoma cells. We suggest that Lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human melanoma.
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a novel dietary triterpene Lupeol induces fas mediated apoptotic death of androgen sensitive prostate cancer cells and inhibits tumor growth in a xenograft model
Cancer Research, 2005Co-Authors: Mohammad Saleem, Vaqar M Adhami, Naghma Khan, Jungmi Yun, Meehyang Kweon, Deeba N Syed, Hasan MukhtarAbstract:In prostate cancer, a fine balance between cell proliferation and apoptotic death is lost, resulting in increased cellular mass and tumor progression. One approach to redress this imbalance and control this malignancy is its preventive intervention through the use of dietary natural agents. Here, we investigated the growth-inhibitory effect and associated mechanisms of Lupeol, a triterpene present in fruits and vegetables, in androgen-sensitive human prostate cancer cells. Lupeol treatment resulted in significant inhibition of cell viability in a dose-dependent manner and caused apoptotic death of prostate cancer cells. Lupeol was found to induce the cleavage of poly(ADP-ribose) polymerase protein and degradation of acinus protein with a significant increase in the expression of FADD protein. Among all death receptor targets examined, Lupeol specifically caused a significant increase in the expression of Fas receptor. The small interfering RNA-mediated silencing of the Fas gene and inhibition of caspase-6, caspase-8, and caspase-9 by their specific inhibitors confirmed that Lupeol specifically activates the Fas receptor-mediated apoptotic pathway in androgen-sensitive prostate cancer cells. The treatment of cells with a combination of anti-Fas monoclonal antibody and Lupeol resulted in higher cell death compared with the additive effect of the two compounds alone, suggesting a synergistic effect. Lupeol treatment resulted in a significant inhibition in growth of tumors with concomitant reduction in prostate-specific antigen secretion in athymic nude mice implanted with CWR22Rnu1 cells. Because early clinical prostate cancer growth is an androgen-dependent response, the results of the present study suggest that Lupeol may have a potential to be an effective agent against prostate cancer.
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Lupeol a fruit and vegetable based triterpene induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of ras signaling pathway
Carcinogenesis, 2005Co-Authors: Mohammad Saleem, Vaqar M Adhami, Meehyang Kweon, Farrukh Afaq, Satwinderjeet Kaur, Hasan MukhtarAbstract: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.
Yogeshwer Shukla - One of the best experts on this subject based on the ideXlab platform.
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induction of apoptosis by Lupeol in human epidermoid carcinoma a431 cells through regulation of mitochondrial akt pkb and nfkappab signaling pathways
Cancer Biology & Therapy, 2009Co-Authors: Sahdeo Prasad, Nidhi Nigam, Jasmine George, Esha Madan, Preeti Roy, Yogeshwer ShuklaAbstract:The rising incidence of skin cancer in humans makes it equivalent to malignancies of organs. Therefore, it is necessary to intensify our efforts for better understanding and development of novel treatment and preventive approaches for skin cancer. Fruits and other plant derived products have gained considerable attention as they can reduce the risk of several cancer types. Lupeol, a triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. In the present study, apoptosis inducing effects of Lupeol were studied in human epidermoid carcinoma A431 cells. Cell cycle analysis showed that Lupeol treatment induces apoptosis (14-37%) in a dose-dependent manner as evident by an increased sub G(1) cell population. The RT-PCR and Western blot analysis showed that Lupeol-induced apoptosis was associated with caspase dependent mitochondrial cell death pathway through activation of Bax, caspases, Apaf1, decrease in Bcl-2 expression and subsequent cleavage of PARP. Lupeol treatment also inhibited Akt/PKB signaling pathway by inhibition of Bad (Ser136) phosphorylation and 14-3-3 expression. In addition, Lupeol treatment inhibited cell survival by inactivation of NFkappaB through upregulation of its inhibitor Ikappabetaalpha. The Caspase mediated apoptosis was noticed by decrease in Lupeol induced apoptosis by Caspase inhibitors as well as increase in reactive oxygen species generation and loss of mitochondrial membrane potential. These results suggest that Lupeol could be an effective anti-cancer agent and merits further investigation.
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Lupeol induces p53 and cyclin b mediated g2 m arrest and targets apoptosis through activation of caspase in mouse skin
Biochemical and Biophysical Research Communications, 2009Co-Authors: Nidhi Nigam, Sahdeo Prasad, Jasmine George, Yogeshwer ShuklaAbstract:Lupeol, present in fruits and medicinal plants, is a biologically active compound that has been shown to have various pharmacological properties in experimental studies. In the present study, we demonstrated the modulatory effect of Lupeol on 7,12-dimethylbenz[a]anthracene (DMBA)-induced alterations on cell proliferation in the skin of Swiss albino mice. Lupeol treatment showed significant (p < 0.05) preventive effects with marked inhibition at 48, 72, and 96 h against DMBA-mediated neoplastic events. Cell-cycle analysis showed that Lupeol-induced G2/M-phase arrest (16-37%) until 72 h, and these inhibitory effects were mediated through inhibition of the cyclin-B-regulated signaling pathway involving p53, p21/WAF1, cdc25C, cdc2, and cyclin-B gene expression. Further Lupeol-induced apoptosis was observed, as shown by an increased sub-G1 peak (28%) at 96 h, with upregulation of bax and caspase-3 genes and downregulation of anti-apoptotic bcl-2 and survivin genes. Thus, our results indicate that Lupeol has novel anti-proliferative and apoptotic potential that may be helpful in designing strategies to fight skin cancer.
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regulation of signaling pathways involved in Lupeol induced inhibition of proliferation and induction of apoptosis in human prostate cancer cells
Molecular Carcinogenesis, 2008Co-Authors: Sahdeo Prasad, Nidhi Nigam, Neetu Kalra, Yogeshwer ShuklaAbstract:Prostate cancer (PCa) is the most frequently diagnosed noncutaneous cancer and the leading cause of cancer related deaths in men in the United States and many other Asian countries. Dietary factors are considered as a strategic agent to control the risk of PCa. Lupeol, a triterpene, present in fruits and medicinal plants, has been shown to possess many pharmacological properties including anticancer effects. Here, effect of Lupeol on cell proliferation and cell death was evaluated using human PCa cells, PC-3. In MTT assay, Lupeol inhibited the cell proliferation (12-71%) in dose (50-800 microM) and time dependent manner. Flow-cytometric analysis of cell-cycle revealed that an antiproliferative effect of Lupeol (400-600 microM) is associated with an increase in G(2)/M-phase arrest (34-58%). RT-PCR analysis showed that Lupeol-induced G2/M-phase arrest was mediated through the inhibition of cyclin regulated signaling pathway. Lupeol inhibited the expression of cyclin B, cdc25C, and plk1 but induced the expression of 14-3-3sigma genes. However no changes were observed in the expression of gadd45, p21(waf1/cip1) and cdc2 genes. Results of western blot showed that Lupeol regulates the phosphorylation of cdc2 (Tyr15) and cdc25C (Ser198). Further, on increase of Lupeol exposure to PC-3 cells an induction of apoptosis was recorded, which was associated with upregulation of bax, caspase-3, -9, and apaf1 genes and down regulation of antiapoptotic bcl-2 gene. The role of caspase-induced apoptosis was confirmed by increase in reactive oxygen species, loss of mitochondrial membrane potential followed by DNA fragmentation. Thus, our study suggests that Lupeol possess novel antiproliferative and apoptotic potential against PCa.
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Lupeol connotations for chemoprevention
Cancer Letters, 2008Co-Authors: Pranav Kumar Chaturvedi, Kulpreet Bhui, Yogeshwer ShuklaAbstract:The perception of chemoprevention lies still in its infancy. Intervention, to slow down, arrest or reverse the process of carcinogenesis, by the use of either natural or synthetic substances individually or in combination therapy has emerged as a promising and pragmatic medical approach to reduce cancer risk. Pentacyclic lupane-type triterpenes exemplified by Lupeol [lup-20(29)-en-3b-ol], are principally found in common fruit plants such as olive, mango, fig, etc. Although, Lupeol exhibits an array of biological activities like anti-inflammatory, anti-arthritic, anti-mutagenic and anti-malarial activity both in in vitro and in vivo systems yet, extensive exploration in regard to establish its role as chemopreventive compound is warranted. Interest in developing Lupeol based potent anti-neoplastic agents, has led to the discovery of a host of highly active derivatives exhibiting greater potencies and better therapeutic indices. This review asserts on the chemopreventive prospects of Lupeol and reveals potential chemoprevention drug targets, central to which are the cell cycle regulatory pathway genes and tries to explain the mechanism operating behind its action.
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protective effects of Lupeol and mango extract against androgen induced oxidative stress in swiss albino mice
Asian Journal of Andrology, 2008Co-Authors: Sahdeo Prasad, Neetu Kalra, Madhulika Singh, Yogeshwer ShuklaAbstract:Aim: To investigate antioxidant potential of Lupeol/mango pulp extract (MPE) in testosterone induced oxidative stress in prostate of male Swiss albino mice. Methods: Oral treatment of Lupeol (1 mg/animal) and MPE (1 mL [20% w/v]/ animal) was given separately to animals along with subcutaneous injection of testosterone (5 mg/kg body weight) consecutively for 15 days. At the end of the study period, the prostate was dissected out for the determination of reactive oxygen species (ROS) levels, lipid peroxidation and antioxidant enzymes status (catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase). Results: In testosterone treated animals, increased ROS resulted in depletion of antioxidant enzymes and increase in lipid peroxidation in mouse prostate. However, Lupeol/MPE treatment resulted in a decrease in ROS levels with restoration in the levels of lipid peroxidation and antioxidant enzymes. Conclusion: The results of the present study demonstrate that Lupeol/MPE are effective in combating oxidative stress-induced cellular injury of mouse prostate. Mango and its constituents, therefore, deserve study as a potential chemopreventive agent against prostate cancer.
Vaqar M Adhami - One of the best experts on this subject based on the ideXlab platform.
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the dietary terpene Lupeol targets colorectal cancer cells with constitutively active wnt β catenin signaling
Molecular Nutrition & Food Research, 2013Co-Authors: Rohinton Tarapore, Vaqar M Adhami, Imtiaz A Siddiqui, Vladimir S Spiegelman, Hasan MukhtarAbstract:Scope Aberrant activation of the Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin signaling pathway is the most common modification, and often considered, a hallmark of colorectal cancer (CRC). Typically in this pathway the β-catenin translocates from the cytoplasm to the nucleus, where it functions as a transcription regulator of several genes that support tumor formation and progression. Thus, any agent that could attenuate the translocation of β-catenin could be extremely valuable against CRC, especially the tumors that exhibit constitutively active Wnt/β-catenin signaling. Methods and results Using human CRC cells that exhibit differential expression of Wnt/β-catenin signaling, we demonstrate that treatment of CRC cells with dietary triterpene Lupeol results in a dose-dependent (i) decrease in cell viability, (ii) induction of apoptosis, (iii) decrease in colonogenic potential, (iv) decrease in β-catenin transcriptional activity, and (v) decrease in the expression of Wnt target genes. Most importantly Lupeol was observed to inhibit the translocation of β-catenin from the cytoplasm to the nucleus. Importantly, all these effects of Lupeol were restricted to cells that harbor constitutively active Wnt/β-catenin signaling while negligible effects were observed in cells that lack constitutively active Wnt/β-catenin signaling. Further, we also demonstrate that inhibition of Wnt signaling in cells with constitutive active Wnt/β-catenin results in loss of Lupeol efficacy while inducing Wnt signaling sensitizes the cells to inhibitory effects of Lupeol. Conclusion In summary, our data strongly advocate the efficacy of Lupeol against CRC cells that exhibit constitutively active Wnt/β-catenin signaling.
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Lupeol inhibits proliferation of human prostate cancer cells by targeting β catenin signaling
Carcinogenesis, 2009Co-Authors: Mohammad Saleem, Imtiyaz Murtaza, Vaqar M Adhami, Naghma Khan, Mohammad Asim, Yewseok Suh, Rohinton Tarapore, Jeremy J Johnson, Imtiaz A Siddiqui, Bilal Bin HafeezAbstract:Lupeol, a dietary triterpene, was shown to decrease serum prostate-specific antigen levels and inhibit the tumorigenicity of prostate cancer (CaP) cells in vivo. Here, we show that Lupeol inhibits the proliferative potential of CaP cells and delineated its mechanism of action. Employing a focused microarray of human CaP-associated genes, we found that Lupeol significantly modulates the expression level of genes such as ERBB2, tissue inhibitor of metalloproteinases-3, cyclin D1 and matrix metalloproteinase (MMP)-2 that are known to be associated with proliferation and survival. A common feature of these genes is that all of them are known to either regulate or act as downstream target of β-catenin signaling that is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of β-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of glycogen synthase kinase 3 beta (GSK3β)–axin complex (regulator of β-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of β-catenin), (4) reduced the transcriptional activation of T Cell Factor (TCF) responsive element (marker for β-catenin signaling) in pTK-TCF-Luc-transfected cells and (5) decreased the transcriptional activation of MMP-2 gene in pGL2-MMP-2-Luc-transfected cells. Effects of Lupeol treatment on β-catenin degradation were significantly reduced in CaP cells where axin is knocked down through small interfering RNA transfection and GSK3β activity is blocked. Collectively, these data suggest the multitarget efficacy of Lupeol on β-catenin-signaling network thus resulting in the inhibition CaP cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human CaP.
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suppression of cflip by Lupeol a dietary triterpene is sufficient to overcome resistance to trail mediated apoptosis in chemoresistant human pancreatic cancer cells
Cancer Research, 2009Co-Authors: Imtiyaz Murtaza, Mohammad Saleem, Vaqar M Adhami, Bilal Bin Hafeez, Hasan MukhtarAbstract:Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of Lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy-resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of Lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of Lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with Lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, Lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of Lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that Lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC.
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a novel dietary triterpene Lupeol induces fas mediated apoptotic death of androgen sensitive prostate cancer cells and inhibits tumor growth in a xenograft model
Cancer Research, 2005Co-Authors: Mohammad Saleem, Vaqar M Adhami, Naghma Khan, Jungmi Yun, Meehyang Kweon, Deeba N Syed, Hasan MukhtarAbstract:In prostate cancer, a fine balance between cell proliferation and apoptotic death is lost, resulting in increased cellular mass and tumor progression. One approach to redress this imbalance and control this malignancy is its preventive intervention through the use of dietary natural agents. Here, we investigated the growth-inhibitory effect and associated mechanisms of Lupeol, a triterpene present in fruits and vegetables, in androgen-sensitive human prostate cancer cells. Lupeol treatment resulted in significant inhibition of cell viability in a dose-dependent manner and caused apoptotic death of prostate cancer cells. Lupeol was found to induce the cleavage of poly(ADP-ribose) polymerase protein and degradation of acinus protein with a significant increase in the expression of FADD protein. Among all death receptor targets examined, Lupeol specifically caused a significant increase in the expression of Fas receptor. The small interfering RNA-mediated silencing of the Fas gene and inhibition of caspase-6, caspase-8, and caspase-9 by their specific inhibitors confirmed that Lupeol specifically activates the Fas receptor-mediated apoptotic pathway in androgen-sensitive prostate cancer cells. The treatment of cells with a combination of anti-Fas monoclonal antibody and Lupeol resulted in higher cell death compared with the additive effect of the two compounds alone, suggesting a synergistic effect. Lupeol treatment resulted in a significant inhibition in growth of tumors with concomitant reduction in prostate-specific antigen secretion in athymic nude mice implanted with CWR22Rnu1 cells. Because early clinical prostate cancer growth is an androgen-dependent response, the results of the present study suggest that Lupeol may have a potential to be an effective agent against prostate cancer.
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Lupeol a fruit and vegetable based triterpene induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of ras signaling pathway
Carcinogenesis, 2005Co-Authors: Mohammad Saleem, Vaqar M Adhami, Meehyang Kweon, Farrukh Afaq, Satwinderjeet Kaur, Hasan MukhtarAbstract: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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retraction note to Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer pcna 1 cells through akt erk pathways
Naunyn-schmiedebergs Archives of Pharmacology, 2021Co-Authors: Yan Liu, Gang Wang, Wei Dai, Liqiang Qian, Quangen Gao, Genhai ShenAbstract:Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anti-cancer activities both in vitro and in vivo. However, the precise mechanism involved remains largely unknown. The present study is conducted to investigate the anti-cancer activity and the underlying mechanisms of Lupeol on human pancreatic cancer proliferating cell nuclear antigen 1 (PCNA-1) cells in vitro and in vivo. Lupeol significantly inhibited the proliferation of the cells in dose- and time-dependent manners and induced apoptosis as well as cell cycle arrest in G0/G1 phase by upregulating P21 and P27 and downregulating cyclin D1. The expression of apoptosis-related proteins in cells was evaluated by western blot analysis, and we found that Lupeol induced cell apoptosis by decreasing the levels of p-AKT and p-ERK. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Lupeol in PCNA-1 cells, demonstrating the important role of AKT in this process. More importantly, our in vivo studies showed that administration of Lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the downregulation of p-AKT and p-ERK in tumor tissues following Lupeol treatment, consistent with the in vitro results. Therefore, these findings indicate that Lupeol can inhibit cell proliferation and induce apoptosis as well as cell cycle arrest of PCNA-1 cells and might offer a therapeutic potential advantage for human pancreatic cancer chemoprevention or chemotherapy.
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Lupeol induces apoptosis and cell cycle arrest of human osteosarcoma cells through pi3k akt mtor pathway
Technology in Cancer Research & Treatment, 2016Co-Authors: Yan Liu, Gang Wang, Wei Dai, Liqiang Qian, Genhai Shen, Quangen GaoAbstract:Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anticancer effect in vitro and in vivo However, the activity of Lupeol against osteosarcoma remains unclear. The present study is conducted to investigate the anticancer activity and the underlying mechanisms of Lupeol on human osteosarcoma cells (MNNG/HOS and MG-63) in vitro and in vivo MNNG/HOS and MG-63 cells were treated by Lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst staining, annexin V/propidium iodide double staining, cell cycle analysis, and Western blot analysis. In addition, MNNG/HOS xenograft tumors were established in female nude BALB/c mice, and Lupeol was intravenously administered to evaluate the anticancer capacity in vivo Our results showed that Lupeol induced apoptosis as well as cell cycle arrest in G0/G1 phase of MNNG/HOS and MG-63 cells in a dose-dependent manner in vitro Furthermore, the protein expression levels of phospho-phosphatidylinositol 3-kinase (p-PI3K), phospho-protein kinase B (p-AKT), p-p70S6K, and cyclin D1 were significantly downregulated, whereas the expression levels of p21 and p27 were upregulated. These protein interactions may play a pivotal role in the regulation of apoptosis and cell cycle arrest. More importantly, our in vivo studies showed that administration of Lupeol decreased tumor growth in a dose-dependent manner and has no significant effect on the function of liver and kidney. Taken together, our findings indicated that Lupeol can induce apoptosis as well as cell cycle arrest of human osteosarcoma cells through phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway and might offer a promising new approach in the effective treatment of osteosarcoma.
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Lupeol induces apoptosis and inhibits invasion in gallbladder carcinoma gbc sd cells by suppression of egfr mmp 9 signaling pathway
Cytotechnology, 2016Co-Authors: Yan Liu, Liqiang Qian, Genhai Shen, Zheng Wang, Quangen GaoAbstract:The cytostatic drug from fruits and other plant derived products have acted as a chemotherapeutic agent used in treatment of a wide variety of cancers. Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. However, the cancer proliferative and invasive inhibitory effects and molecular mechanisms on gallbladder carcinoma GBC-SD cells have not been studied. In the present study, GBC-SD cells were treated by Lupeol and subjected to methyl thiazolyl tetrazolium analysis, Hoechst 33342 staining, annexin V/propidium iodide double-staining, transwell chamber assay and Western blot analysis. In addition, GBC-SD xenograft tumors were established in male nude BALB/c mice, and Lupeol was intravenously administered to evaluate the anti-cancer capacity in vivo. Our results showed that Lupeol inhibited the proliferation, migration, invasion and induced apoptosis of GBC-SD cells in a dose-dependent manner in vitro. Furthermore, the expression of p-EGFR, p-AKT and MMP-9 levels were significantly down-regulated. These protein interactions may play a pivotal role in the regulation of apoptosis and invasion. More importantly, our in vivo studies showed that administration of Lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the down-regulation of p-EGFR and MMP-9 in tumor tissues following Lupeol treatment, consistent with the in vitro results. Taken together, our findings indicated that Lupeol can induce apoptotic cell death and inhibit the migration as well as invasion of GBC-SD cells. The mechanism may be associated with the suppression of EGFR/MMP-9 signaling. These results might offer a therapeutic potential advantage for human gallbladder carcinoma chemoprevention or chemotherapy.
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Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer pcna 1 cells through akt erk pathways
Naunyn-schmiedebergs Archives of Pharmacology, 2015Co-Authors: Yan Liu, Gang Wang, Wei Dai, Liqiang Qian, Quangen Gao, Genhai ShenAbstract:Lupeol, a dietary triterpene, present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including anti-cancer activities both in vitro and in vivo. However, the precise mechanism involved remains largely unknown. The present study is conducted to investigate the anti-cancer activity and the underlying mechanisms of Lupeol on human pancreatic cancer proliferating cell nuclear antigen 1 (PCNA-1) cells in vitro and in vivo. Lupeol significantly inhibited the proliferation of the cells in dose- and time-dependent manners and induced apoptosis as well as cell cycle arrest in G0/G1 phase by upregulating P21 and P27 and downregulating cyclin D1. The expression of apoptosis-related proteins in cells was evaluated by western blot analysis, and we found that Lupeol induced cell apoptosis by decreasing the levels of p-AKT and p-ERK. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Lupeol in PCNA-1 cells, demonstrating the important role of AKT in this process. More importantly, our in vivo studies showed that administration of Lupeol decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the downregulation of p-AKT and p-ERK in tumor tissues following Lupeol treatment, consistent with the in vitro results. Therefore, these findings indicate that Lupeol can inhibit cell proliferation and induce apoptosis as well as cell cycle arrest of PCNA-1 cells and might offer a therapeutic potential advantage for human pancreatic cancer chemoprevention or chemotherapy.
