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Search Results: 1 - 10 of 33014 matches for " Q. Ping Dou "
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Tea Polyphenols and Their Roles in Cancer Prevention and Chemotherapy
Di Chen,Q. Ping Dou
International Journal of Molecular Sciences , 2008, DOI: 10.3390/ijms9071196
Abstract: Many plant-derived, dietary polyphenols have been studied for their chemopreventive and chemotherapeutic properties against human cancers, including green tea polyphenols, genistein (found in soy), apigenin (celery, parsley), luteolin (broccoli), quercetin (onions), kaempferol (broccoli, grapefruits), curcumin (turmeric), etc. The more we understand their involved molecular mechanisms and cellular targets, the better we could utilize these “natural gifts” for the prevention and treatment of human cancer. Furthermore, better understanding of their structure-activity relationships will guide synthesis of analog compounds with improved bio-availability, stability, potency and specificity. This review focuses on green tea polyphenols and seeks to summarize several reported biological effects of tea polyphenols in human cancer systems, highlight the molecular targets and pathways identified, and discuss the role of tea polyphenols in the prevention and treatment of human cancer. The review also briefly describes several other dietary polyphenols and their biological effects on cancer prevention and chemotherapy.
Tea Polyphenols and Their Roles in Cancer Prevention and Chemotherapy
Di Chen,Q. Ping Dou
International Journal of Molecular Sciences , 2008,
Abstract: Many plant-derived, dietary polyphenols have been studied for their chemopreventive and chemotherapeutic properties against human cancers, including green tea polyphenols, genistein (found in soy), apigenin (celery, parsley), luteolin (broccoli), quercetin (onions), kaempferol (broccoli, grapefruits), curcumin (turmeric), etc. The more we understand their involved molecular mechanisms and cellular targets, the better we could utilize these ¢ € natural gifts ¢ € for the prevention and treatment of human cancer. Furthermore, better understanding of their structure-activity relationships will guide synthesis of analog compounds with improved bio-availability, stability, potency and specificity. This review focuses on green tea polyphenols and seeks to summarize several reported biological effects of tea polyphenols in human cancer systems, highlight the molecular targets and pathways identified, and discuss the role of tea polyphenols in the prevention and treatment of human cancer. The review also briefly describes several other dietary polyphenols and their biological effects on cancer prevention and chemotherapy.
Use of proteasome inhibitors in anticancer therapy
Sara M. Schmitt,Lillian Lu,Q. Ping Dou
Reviews in Health Care , 2011, DOI: 10.7175/rhc.6024259-287
Abstract: The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (-)-EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.
Activation of AMP-Activated Protein Kinase by 3,3′-Diindolylmethane (DIM) Is Associated with Human Prostate Cancer Cell Death In Vitro and In Vivo
Di Chen, Sanjeev Banerjee, Qiuzhi C. Cui, Dejuan Kong, Fazlul H. Sarkar, Q. Ping Dou
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047186
Abstract: There is a large body of scientific evidence suggesting that 3,3′-Diindolylmethane (DIM), a compound derived from the digestion of indole-3-carbinol, which is abundant in cruciferous vegetables, harbors anti-tumor activity in vitro and in vivo. Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic. We previously reported that a formulated DIM (BR-DIM; hereafter referred as B-DIM) with higher bioavailability was able to induce apoptosis and inhibit cell growth, angiogenesis, and invasion of prostate cancer cells. However, the precise molecular mechanism(s) for the anti-cancer effects of B-DIM have not been fully elucidated. In the present study, we investigated whether AMP-activated protein kinase (AMPK) is a molecular target of B-DIM in human prostate cancer cells. Our results showed, for the first time, that B-DIM could activate the AMPK signaling pathway, associated with suppression of the mammalian target of rapamycin (mTOR), down-regulation of androgen receptor (AR) expression, and induction of apoptosis in both androgen-sensitive LNCaP and androgen-insensitive C4-2B prostate cancer cells. B-DIM also activates AMPK and down-regulates AR in androgen-independent C4-2B prostate tumor xenografts in SCID mice. These results suggest that B-DIM could be used as a potential anti-cancer agent in the clinic for prevention and/or treatment of prostate cancer regardless of androgen responsiveness, although functional AR may be required.
Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells
Kenyon G Daniel, Di Chen, Shirley Orlu, Qiuzhi Cui, Fred R Miller, Q Ping Dou
Breast Cancer Research , 2005, DOI: 10.1186/bcr1322
Abstract: Breast cell lines, normal, immortalized MCF-10A, premalignant MCF10AT1K.cl2, and malignant MCF10DCIS.com and MDA-MB-231, were treated with CQ or PDTC with or without prior interaction with copper, followed by measurement of proteasome inhibition and cell death. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity and ubiquitinated proteins in protein extracts of the treated cells. Apoptotic cell death was measured by morphological changes, Hoechst staining, and poly(ADP-ribose) polymerase cleavage.When in complex with copper, both CQ and PDTC, but not TM, can inhibit the proteasome chymotrypsin-like activity, block proliferation, and induce apoptotic cell death preferentially in breast cancer cells, less in premalignant breast cells, but are non-toxic to normal/non-transformed breast cells at the concentrations tested. In contrast, CQ, PDTC, TM or copper alone had no effects on any of the cells. Breast premalignant or cancer cells that contain copper at concentrations similar to those found in patients, when treated with just CQ or PDTC alone, but not TM, undergo proteasome inhibition and apoptosis.The feature of breast cancer cells and tissues to accumulate copper can be used as a targeting method for anticancer therapy through treatment with novel compounds such as CQ and PDTC that become active proteasome inhibitors and breast cancer cell killers in the presence of copper.Copper is an essential trace metal for animals. The amount of copper in an organism is tightly regulated [1,2]. Angiogenesis, the growth of a tumor blood supply, is essential for tumor growth, invasion, and metastasis [3-6]. It has been shown that tumors, without a blood supply, do not grow larger than 1 to 2 mm3 [7]. Molecular processes of angiogenesis that require copper as an essential cofactor include stimulation of endothelial growth by tumor cytokine production (i.e., vasoendothelial growth factor), degradation of extracellular matrix proteins
Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts
Di Chen, Kristin R Landis-Piwowar, Marina S Chen, Q Ping Dou
Breast Cancer Research , 2007, DOI: 10.1186/bcr1797
Abstract: MDA-MB-231 breast cancer cell cultures and xenografts were treated with apigenin, followed by measurement of reduced cellular viability/proliferation, proteasome inhibition, and apoptosis induction. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity, by ubiquitinated proteins, and by accumulation of proteasome target proteins in extracts of the treated cells or tumors. Apoptotic cell death was measured by capase-3/caspase-7 activation, poly(ADP-ribose) polymerase cleavage, and immunohistochemistry for terminal nucleotidyl transferase-mediated nick end labeling positivity.We report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis not only in cultured MDA-MB-231 cells but also in MDA-MB-231 xenografts. Furthermore, while apigenin has antibreast tumor activity, no apparent toxicity to the tested animals was observed.We have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts. Furthermore, apigenin induces apoptotic cell death in human breast cancer cells and exhibits anticancer activities in tumors. The results suggest its potential benefits in breast cancer prevention and treatment.Regular consumption of a variety of polyphenolic compounds has been associated with reduced cancer risk and with tumor growth suppression [1]. The polyphenolic flavone apigenin is widely distributed among fruits and vegetables, and apigenin has been shown to possess chemopreventive activities in a number of cancer models including those of lung cancer [2], skin cancer [3], cervical cancer [4], prostate cancer [5], and leukemia [6]. The mechanisms by which apigenin imparts its anticancer effects are varied and may include action through antiinflammation [7], free radical scavenging [8], and proteasome inhibition [6,9].The eukaryotic proteasome is a large multicatalytic, multisubunit protease complex possessing at least
Gold(III)-Dithiocarbamato Peptidomimetics in the Forefront of the Targeted Anticancer Therapy: Preclinical Studies against Human Breast Neoplasia
Chiara Nardon, Sara M. Schmitt, Huanjie Yang, Jian Zuo, Dolores Fregona, Q. Ping Dou
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084248
Abstract: Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg?1 d?1, compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.
Withaferin A Inhibits the Proteasome Activity in Mesothelioma In Vitro and In Vivo
Huanjie Yang,Ying Wang,Vino T. Cheryan,Wenjuan Wu,Cindy Qiuzhi Cui,Lisa A. Polin,Harvey I. Pass,Q. Ping Dou,Arun K. Rishi,Anil Wali
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041214
Abstract: The medicinal plant Withania somnifera has been used for over centuries in Indian Ayurvedic Medicine to treat a wide spectrum of disorders. Withaferin A (WA), a bioactive compound that is isolated from this plant, has anti-inflammatory, immuno-modulatory, anti-angiogenic, and anti-cancer properties. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of WA and the molecular mechanisms involved. WA inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in increased levels of ubiquitinated proteins and pro-apoptotic proteasome target proteins (p21, Bax, IκBα). WA suppression of MPM growth also involved elevated apoptosis as evidenced by activation of pro-apoptotic p38 stress activated protein kinase (SAPK) and caspase-3, elevated levels of pro-apoptotic Bax protein and cleavage of poly-(ADP-ribose)-polymerase (PARP). Our studies including gene-array based analyses further revealed that WA suppressed a number of cell growth and metastasis-promoting genes including c-myc. WA treatments also stimulated expression of the cell cycle and apoptosis regulatory protein (CARP)-1/CCAR1, a novel transducer of cell growth signaling. Knock-down of CARP-1, on the other hand, interfered with MPM growth inhibitory effects of WA. Intra-peritoneal administration of 5 mg/kg WA daily inhibited growth of murine MPM cell-derived tumors in vivo in part by inhibiting proteasome activity and stimulating apoptosis. Together our in vitro and in vivo studies suggest that WA suppresses MPM growth by targeting multiple pathways that include blockage of proteasome activity and stimulation of apoptosis, and thus holds promise as an anti-MPM agent.
Prodrugs of Fluoro-Substituted Benzoates of EGC as Tumor Cellular Proteasome Inhibitors and Apoptosis Inducers
Zhiyong Yu,Xu Long Qin,Yan Yan Gu,Di Chen,Qiuzhi Cindy Cui,Tao Jiang,Sheng Biao Wan,Q. Ping Dou
International Journal of Molecular Sciences , 2008, DOI: 10.3390/ijms9060951
Abstract: The most potent catechin in green tea is (-)-epigallocatechin-3-gallate [(-)- EGCG], which, however, is unstable under physiological conditions. To discover more stable and more potent polyphenol proteasome inhibitors, we synthesized several novel fluoro-substituted (-)-EGCG analogs, named F-EGCG analogs, as well as their prodrug forms with all of -OH groups protected by acetate. We report that the prodrug form of one F-EGCG analog exhibited greater potency than the previously reported peracetate of (-)- EGCG to inhibit proteasomal activity, suppress cell proliferation, and induce apoptosis in human leukemia Jurkat T cells, demonstrating the potential of these compounds to be developed into novel anti-cancer and cancer-preventive agents.
HDAC Inhibitor L-Carnitine and Proteasome Inhibitor Bortezomib Synergistically Exert Anti-Tumor Activity In Vitro and In Vivo
Hongbiao Huang, Ningning Liu, Changshan Yang, Siyan Liao, Haiping Guo, Kai Zhao, Xiaofen Li, Shouting Liu, Lixia Guan, Chunjiao Liu, Li Xu, Change Zhang, Wenbin Song, Bing Li, Ping Tang, Q. Ping Dou, Jinbao Liu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052576
Abstract: Combinations of proteasome inhibitors and histone deacetylases (HDAC) inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC) is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel) was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like) activity assay. Here we report that (i) the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii) the combination also synergistically inhibits tumor growth in vivo; (iii) two major pathways are involved in the synergistical effects of the combinational treatment: increased p21cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.
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