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Yiwei Li

Publications and source records attributed to Yiwei Li.

At least 37 records · Page 2Linked to original sources
PubMed2006

The role of genistein and synthetic derivatives of isoflavone in cancer prevention and therapy.

Genistein, one of the predominant soy isoflavones, has been shown to compete with 17beta-estradiol for estrogen receptor binding because of its structural similarity, resulting in agonistic or antagonistic activity. It causes inhibition of cell growth in breast and prostate cancers in vivo and in vitro. From gene expression profiles, genistein has been found to regulate the genes that are critical for the control of cell proliferation, cell cycle, apoptosis, oncogenesis, transcription regulation, and cell signal transduction pathways. It has been reported that genistein induces apoptosis and inhibits activation of NF-kappaB and Akt signaling pathways, both of which are known to maintain a balance between cell survival and apoptosis. Recently, we found that genistein sensitized cancer cells to apoptosis induced by chemotherapeutic agents including docetaxel, gemcitabine and cisplatin through inactivation of NF-kappaB in multiple cancer cell lines. To enhance the anti-cancer activity of genistein, we have synthesized structurally-modified derivatives of isoflavone based on the structural requirements for optimal anti-cancer effect. We found that these synthetic derivatives of isoflavone exerted higher anti-cancer activity with lower IC50. These derivatives of isoflavone also induced more apoptosis compared to genistein. These results suggest that genistein and synthetic structurally-modified derivatives of isoflavone may be promising agents for cancer chemoprevention and therapy either alone or in combination with existing chemotherapeutic agents.

Breast Neoplasms↗
PubMed2005

Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.

Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor kappaB (NF-kappaB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-kappaB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-kappaB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 micromol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 micromol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-kappaB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-kappaB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-kappaB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-kappaB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Gene expression profiling revealed novel mechanism of action of Taxotere and Furtulon in prostate cancer cells.

BACKGROUND: Both Taxotere and Capecitabine have shown anti-cancer activity against various cancers including prostate cancer. In combination, Taxotere plus Capecitabine has demonstrated higher anti-cancer activity in advanced breast cancers. However, the molecular mechanisms of action of Taxotere and Capecitabine have not been fully elucidated in prostate cancer. METHODS: The total RNA from PC3 and LNCaP prostate cells untreated and treated with 2 nM Taxotere, 110 microM Furtulon (active metabolite of Capecitabine), or 1 nM Taxotere plus 50 microM Furtulon for 6, 36, and 72 hours, was subjected to Affymetrix Human Genome U133A Array analysis. Real-time PCR and Western Blot analysis were conducted to confirm microarray data. RESULTS: Taxotere and Furtulon down-regulated some genes critical for cell proliferation, cell cycle progression, transcription factor, cell signaling, and oncogenesis, and up-regulated some genes related to the induction of apoptosis, cell cycle arrest, and differentiation in both cell lines. Taxotere and Furtulon also up-regulated some genes responsible for chemotherapeutic resistance, suggesting the induction of cancer cell resistance to these agents. CONCLUSIONS: Taxotere and Furtulon caused the alternation of a large number of genes, many of which may contribute to the molecular mechanisms by which Taxotere and Furtulon inhibit the growth of prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.

Antineoplastic Agents↗
PubMed2005

Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells.

Prostate cancer is the second leading cause of cancer related deaths in men in the United States. I3C and its in vivo dimeric product, DIM, have been found to inhibit the growth of prostate cancer cells. However, the molecular mechanism(s) by which DIM elicits its effects on prostate cancer cells has not been fully elucidated. We have previously shown that I3C induces apoptosis and inhibits the activation of NF-kappaB pathway, which could be mediated via Akt signaling pathway. In this study, we investigated whether there is any cross-talk between Akt and NF-kappaB during DIM-induced apoptosis in PC-3 prostate cancer cells. We found that DIM inhibited cell growth and induced apoptosis in PC-3 prostate cancer cells but not in non-tumorigenic CRL2221 human prostate epithelial cells. DIM also inhibited EGFR expression, PI3K kinase activity, and Akt activation, and abrogated the EGF-induced activation of PI3K in prostate cancer cells. NF-kappaB DNA-binding analysis and transfection studies with Akt cDNA constructs revealed that Akt transfection resulted in the induction of NF-kappaB activity and this was inhibited by DIM treatment. DIM treatment also showed significant induction of apoptosis in non-transfected cells compared to Akt and Akt-Myr transfected prostate cancer cells. From these results, we conclude that the inhibition of Akt and NF-kappaB activity and their cross-talk is a novel mechanism by which DIM inhibits cell growth and induces apoptotic processes in prostate cancer cells but not in non-tumorigenic prostate epithelial cells.

Apoptosis↗
PubMed2005

Quantitative chemiluminescent immunoassay for NF-kappaB-DNA binding activity.

Nuclear factor-kappaB (NF-kappaB) is a ubiquitous redox-sensitive transcription factor involved in the pro-inflammatory response to several factors, including cytokines and oxidative stress. Upon activation, NF-kappaB translocates into the nucleus and binds to specific nucleotide sequences. The cellular responses to inflammatory and stress signals have been implicated in disease conditions, such as atherosclerosis, cancer, diabetes, and Alzheimer's disease. The conventional method for detection of NF-kappaB -DNA binding activity is the electrophoretic mobility shift assay (EMSA), which is time-consuming and non-quantitative. Here, we report (a) development of a rapid, sensitive and quantitative chemiluminescent immunoassay (QCI) for analysis of NF-kappaB DNA-binding activity, and (b) validation of the QCI with the EMSA using nuclear and cytosolic extracts from cultured prostate cancer cells (PC3), rat liver homogenates and human lymphocytes. The QCI for analysis of NF-kappaB DNA binding activity has advantages over the EMSA: (1) Higher speed: 3-5h post sample preparation, (2) Greater sensitivity: 10pg NF-kappaB/well, (3) Quantitative: linear range: 10-1000pg NF-kappaB; r2 = 0.999 (4) High throughput adaptability: 96-well plate format can analyze up to 40 samples in duplicate, (5) SAFETY: No radioactive isotopes, (6) Simplicity, and (7) Capability of measurement of both activated (free) NF-KB which is translocated into the nucleus and total (bound + unbound) NF-kappaB present in the cytosol/cell.

Animals↗
PubMed2005

Gene expression profiling revealed novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells.

Both docetaxel and estramustine are antimicrotubule agents with antitumor activity in various cancers including prostate cancer. Clinical trials for docetaxel and estramustine combination treatment have suggested improved antitumor activity in hormone-refractory prostate cancer. However, the molecular mechanisms involved in the combination treatment with docetaxel and estramustine have not been fully elucidated. In order to establish such molecular mechanisms in both hormone insensitive (PC-3) and sensitive (LNCaP) prostate cancer cells, gene expression profiles of docetaxel- and estramustine-treated prostate cancer cells were obtained by using Affymetrix Human Genome U133A Array. Total RNA from PC-3 and LNCaP cells untreated and treated with 2 nmol/L docetaxel, 4 micromol/L estramustine, or 1 nmol/L docetaxel plus 2 micromol/L estramustine for 6, 36, and 72 hours was subjected to microarray analysis. Real-time PCR and Western blot analysis were conducted to confirm the microarray data. Clustering analysis based on biological function showed that docetaxel and estramustine combination treatment down-regulated some genes that are known to regulate cell proliferation, transcription, translation, and oncogenesis. In contrast, docetaxel and estramustine combination treatment up-regulated some genes related to induction of apoptosis, cell cycle arrest, and tumor suppression. Docetaxel and estramustine also showed differential effects on gene expression between mono- and combination treatment. Combination treatment with docetaxel and estramustine caused alternations of a large number of genes, many of which may contribute to the molecular mechanisms by which docetaxel and estramustine inhibit the growth of prostate cancer cells. These results provide novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.

Antineoplastic Agents↗
PubMed2005

[Study on proliferation effect of extracts of Piper longum on mesenchymal stem cells of rat bone marrow and the relationship to chemical functional groups].

OBJECTIVE: To observe the effect of volatile oil and aqueous soluable part of Piper longum on proliferation of rat mesenchymal stem cell (MSC) and the chemical functional groups. METHODS: Mesenchymal stem cells were dissociated from rat bone marrow and marked by Brdu, and the expression of CD44, CD54 and double label of Brdu and CD44. The growth of rat mesenchymal stem cell under volatile oil and aqueous soluable part of Piper longum was observed by means of cell viability measurement (MTT) and morphological observation and Brdu, PCNA immunohistochemical methods. RESULTS: Volatile oil of Piper longum could promote the cell viability of MSC and the number of Brdu, PCNA positive cell in dose-dependant. There was significant difference in comparision with control groups, C = C(50.66%), -OH(27.02%) and other functional groups in volatile oil of Piper longum were determined by GC-MS, but the aqueous soluable part of Piper longum could not promote the proliferation of MSC. CONCLUSIONS: Volatile oil of Piper longum which consists of C = C, -OH, and other functional groups has strong effect on enhancing proliferation of MSC.

Animals↗
PubMed2004

Cell signaling pathways altered by natural chemopreventive agents.

Epidemiological studies have indicated a significant difference in the incidence of cancers among ethnic groups, who have different lifestyles and have been exposed to different environmental factors. It has been estimated that more than two-thirds of human cancers, which are contributed by mutations in multiple genes, could be prevented by modification of lifestyle including dietary modification. The consumption of fruits, soybean and vegetables has been associated with reduced risk of several types of cancers. The in vitro and in vivo studies have demonstrated that some dietary components such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), apigenin, etc., have shown inhibitory effects on human and animal cancers, suggesting that they may serve as chemopreventive agents. Experimental studies have also revealed that these components regulate the molecules in the cell signal transduction pathways including NF-kappaB, Akt, MAPK, p53, AR, and ER pathways. By modulating cell signaling pathways, these components, among other mechanisms, activate cell death signals and induce apoptosis in precancerous or cancer cells, resulting in the inhibition of cancer development and/or progression. This article reviews current studies regarding the effects of natural chemopreventive agents on cancer-related cell signaling pathways and provides comprehensive knowledge of the biological and molecular roles of chemopreventive agents in cancer cells.

Animals↗
PubMed2004

The role of isoflavones in cancer chemoprevention.

Cancer is one of the major health problems around the world. However, it has been estimated that more than two-thirds of human cancers could be prevented by modification of lifestyle including dietary modification.The incidences of hormone-related cancers are much higher in Western countries compared to Asian countries. One of the major differences in diet between these populations is that the Asians consume a traditional diet high in isoflavones. Epidemiologic evidence together with data from animal and in vitro studies strongly supports relationship between isoflavones and the lower risk of cancers. Isoflavones have been shown to inhibit carcinogenesis in vivo in animal experiments. It has been known that genistein, one of the major isoflavones, inhibits the growth of various cancer cells through the modulation of genes that are related to the control of cell cycle, apoptosis, and cell signaling pathways. Moreover, genistein has been found to be a potent inhibitor of oxidative stress, angiogenesis, and metastasis.Therefore, isoflavones exert beneficial effects on human health and may be promising agents for cancer prevention and/or treatment. However, further in depth experimental investigations along with clinical trials are needed to fully evaluate the value of isoflavones in human cancer prevention and/or treatment.

Animals↗
PubMed2004

Gene expression profiling reveals novel targets of estramustine phosphate in prostate cancer cells.

Estramustine phosphate (EMP) is a compound widely used for the treatment of hormone-refractory prostate cancer. In order to better understand the precise molecular mechanism(s) by which EMP exerts its effects on hormone-resistant PC3 prostate cancer cells, we have utilized microarray to interrogate 22,215 known genes to determine the gene expression profiles altered by EMP treatment. The purpose of this investigation was to identify gene expression profile first and then in future studies determine the specific role of these genes in EMP-induced apoptosis in prostate cancer cells. We found a total of 726 genes which showed >2 fold change after EMP treatment. Clustering analysis showed 12 different types of expression alteration. These genes were also subjected to cluster analysis according to their biological functions. We found that EMP regulated the expression of genes, which are critically involved in the regulation of cell growth, cell cycle, apoptosis, iron homeostasis, cytoskeleton and cell signaling transduction. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of microarray, and the results of real-time quantitative RT-PCR were consistent with the microarray data. From these results, we conclude that EMP caused changes in the expression of a large number of genes that are related to the control of cell survival and physiological behaviors. The gene expression profiles may provide comprehensive molecular mechanism(s) by which EMP exerts its pleiotropic effects on prostate cancer cells. EMP-induced regulation of these genes may be further exploited for devising therapeutic strategies for prostate cancer.

Estramustine↗
PubMed2004

Indole-3-carbinol and prostate cancer.

Epidemiological and dietary studies have revealed an association between high dietary intake of cruciferous vegetables and decreased prostate cancer risk. Our studies have shown that indole-3-carbinol (I3C), a common phytochemical in cruciferous vegetables, and its in vivo dimeric product 3,3'-diindolylmethane (DIM) upregulate the expression of phase I and phase II enzymes, suggesting increased capacity for detoxification and inhibition of carcinogens. Studies from our laboratory and others have found that I3C can induce G1 cell-cycle arrest and apoptosis in prostate cancer cells. In addition, we found, by microarray gene expression profiling, that I3C and DIM regulate many genes that are important for the control of cell cycle, cell proliferation, signal transduction, and other cellular processes, suggesting the pleiotropic effects of I3C and DIM on prostate cancer cells. We recently found that I3C functions as an inhibitor of Akt and nuclear factor kappaB (NF-kappaB), which play important roles in cell survival and which are believed to be potential targets in cancer therapy. Studies have already shown that the inactivation of Akt and NF-kappaB is responsible for chemosensitization of chemoresistant cancer cells. Because there is no effective treatment strategy for hormone-dependent and, most importantly, hormone-independent and metastatic prostate cancer, our strategies to sensitize prostate cancer cells to a chemotherapeutic agent by I3C and DIM is a novel breakthrough that could be used for devising novel therapies for prostate cancer. In conclusion, the results from our laboratory and from others provide ample evidence for the benefit of I3C and DIM for the prevention and the treatment of prostate cancer.

Apoptosis↗
PubMed2004

Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line.

Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-kappaB activity. In contrast, chemotherapeutic agents inadvertently induce NF-kappaB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-kappaB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 micromol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-kappaB EMSA were performed. The combination of 30 micromol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-kappaB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-kappaB-inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-kappaB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.

Antineoplastic Agents↗
PubMed2004

Inactivation of akt and NF-kappaB play important roles during indole-3-carbinol-induced apoptosis in breast cancer cells.

Despite significant advances in treatment, breast cancer is still the second leading cause of cancer-related deaths in women in the United States. Therefore, significant efforts are being given to develop novel strategies for the prevention of breast cancer in recent years. Our laboratory and others have been studying the effects of a potential chemopreventive agent, indole-3-carbinol (I3C), in breast cancer cells. We have previously shown that I3C induces apoptosis in breast cancer cells and found that the induction of apoptotic processes was partly mediated by dysregulation of anti- and pro-apoptotic molecules. However, the precise molecular mechanism(s) by which I3C induces apoptosis in breast cancer cells has not been fully elucidated. For the present study, we focused our investigation on important cell signaling molecules such as Akt and NF-kappaB during I3C-induced apoptosis in breast cancer cells. We found that I3C induces apoptotic processes in MCF10A-derived cell lines with premalignant (DCIS.com) and malignant (MCF10CA1a) phenotypes but not in nontumorigenic parental MCF10A cells. Immunoprecipitation, kinase assays, and Western blot analysis showed that I3C specifically inhibits Akt kinase activity and abrogates the EGF-induced activation of Akt in breast cancer cells. NF-kappaB DNA-binding analysis and transfection studies with Akt cDNA and NF-kappaB-Luc reporter constructs revealed that Akt gene transfection directly activates NF-kappaB, and this activation was completely abrogated by I3C treatment. In addition, I3C also abrogated the EGF-induced activation of NF-kappaB, which was mediated via the Akt signaling pathway. From these results, we conclude that there is a direct cross-talk between Akt and NF-kappaB pathways and that the inactivation of Akt and NF-kappaB activity plays important roles in mediating I3C-induced apoptosis in breast cancer cells. These results also suggest that I3C may be a potential chemopreventive agent by virtue of its selective apoptosis-inducing ability in premalignant and malignant breast epithelial cells.

Animals↗
PubMed2004

[Effect of niupo zhibao pellet on transforming growth factor-beta1 and its receptor's expression in endotoxic shock rats with lung injury].

OBJECTIVE: To observe the influence of Niupo Zhibao pellet (NZP) on transforming growth factor-beta1 (TGF-beta1) and its receptor's expression. METHODS: Endotoxic shock model was established by intravenous injection of lipopolysaccharide (LPS) 1.5 mg/kg and intraperitoneal injection of D-galactosamine 100 mg/kg, and intervened by NZP, TGF-beta1 and its receptor's expression in lung tissue were detected by immunohistochemical method. RESULTS: NZP could enhance the TGF-beta1 and its receptor's expression in endotoxic shock lung tissue, and reduce the injury of lung. CONCLUSION: The mechanism of NZP in reducing endotoxic shock lung injury is possibly related with its effect in enhancing the TGF-beta1 and its receptor's expression in lung tissue.

Animals↗
PubMed2003

Total synthesis of apoptolidin: construction of enantiomerically pure fragments.

A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.

Macrolides↗
PubMed2003

Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation.

The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.

Antineoplastic Agents↗