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Feihu Chen - One of the best experts on this subject based on the ideXlab platform.
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a novel all trans Retinoic Acid Derivative inhibits proliferation and induces apoptosis of myelodysplastic syndromes cell line skm 1 cells via up regulating p53
International Immunopharmacology, 2018Co-Authors: Yan Du, Lanlan Li, Hao Chen, Cong Wang, Xuewen Qian, Yubin Feng, Lei Zhang, Feihu ChenAbstract:Abstract Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans Retinoic Acid (ATRA) Derivative, play an important role in various types of cancer cells as a tumor inhibitor. However, little is known concerning its antitumor effect on MDS. The cell viability and the percentage of apoptotic cells were used to measure MTT, Flow Cytometry and Hoechst 33342/PI staining. In addition, real-time quantitative RT-PCR (qRT-PCR) and western blotting were used to analyzed the expression of p53, as well as the levels of BNIP3, apoptosis proteins of Caspase-3, BAX and BCL-2. After SKM-1 cells were incubated with DAC, ATRA and ATPR, the viability of the SKM-1 cells was inhibited in a dose- and time-dependent manner. Both Hoechst staining and flow cytometry showed the apoptosis of SKM-1 cells was increased. Moreover, SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53, BNIP3, BAX and Caspase-3 expression and decreased BCL-2 expression. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation.
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a novel all trans Retinoic Acid Derivative 4 amino 2 trifluoromethyl phenyl retinate inhibits the proliferation of human hepatocellular carcinoma hepg2 cells by inducing g0 g1 cell cycle arrest and apoptosis via upregulation of p53 and aspp1 and down
Oncology Reports, 2016Co-Authors: Feihu Chen, Ling Zhang, Qing Zhou, Yuan WangAbstract:Abstract 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans Retinoic Acid (ATRA) Derivative, was reported to function as a tumor inhibitor in various types of cancer cells in vitro. However, little is known concerning its antitumor effect on human hepatocellular carcinoma (HCC) HepG2 cells. The aims of the present study were to investigate the effects of ATPR on the proliferation of HepG2 cells and to explore the probable mechanisms. A series of experiments were performed following the treatment of HepG2 cells with ATRA and ATPR. MTT and plate colony formation assays were used to measure the cell viability. To confirm the influence on proliferation, flow cytometry was used to detect the distribution of the cell cycle. Apoptosis was observed by Hoechst staining and flow cytometry. In addition, to characterize the underlying molecular mechanisms, immunofluorescence was applied to observe the distribution of p53. The transcription and translation levels of p53 were analyzed by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The expression levels of murine double minute 2 (MDM2), apoptosis stimulating proteins of p53 (ASPP), cell cycle- and apoptosis-associated proteins were detected by western blotting. After HepG2 cells were incubated with ATRA and ATPR, the viability of the HepG2 cells was inhibited in a dose- and time-dependent manner. As well, ATPR significantly suppressed HepG2 cell colony formation and arrested cells at the G0/G1 phase, while ATRA had no obvious effects. Both Hoechst staining and flow cytometry unveiled the apoptosis of HepG2 cells. Moreover, the fluorescent density of p53 was higher in the nuclei after exposure to ATPR than that in the ATRA group. HepG2 cells treated with ATPR showed elevated mRNA and protein levels of p53 when compared with these levels in the ATRA-treated cells. Western blotting showed that ATPR increased ASPP1, p21 and Bax expression and decreased MDM2, iASPP, cyclin D and E, cyclin-dependent kinase 6 (CDK6) and Bcl-2 expression, while CDK4 and ASPP2 expression were scarcely altered. Consequently, ATPR exerted a better inhibitory effect on the proliferation of HepG2 cells than ATRA through increased expression of p53 and ASPP1 and downregulation of iASPP, thereby resulting in G0/G1 cell cycle arrest and apoptosis.
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Development of a Rapid and Low Cost Method for Measuring Plasma Protein Binding
Chromatographia, 2015Co-Authors: Jihui Tang, Feihu Chen, Jue Song, Hongmei Zang, Jun LiAbstract:In drug discovery and development, it is very important to investigate the plasma protein binding (PPB) of a drug to better understand its in vivo fate. In this study, a rapid and low-cost solid-phase extraction (SPE) method was developed for determining the PPB. With this method, the total protein recovery of a blank human plasma sample was 83.7 %. The unbound drug was easily adsorbed by an ODS C18 SPE column, and the recovery of three known drugs was more than 90 %. Their PPBs obtained by the SPE were identical to the value reported by conventional techniques. In addition, more than 90 % of 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), which is a novel all-trans Retinoic Acid Derivative (ATRA), was bound to human plasma protein as determined by SPE, and this value was comparable with that obtained by our previously described gel filtration-based method. Considering its versatility, speed of separation, and low cost, SPE is a rapid and economical method for measuring PPB.
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a novel all trans Retinoic Acid Derivative inhibits proliferation and induces differentiation of human gastric carcinoma xenografts via up regulating Retinoic Acid receptor β
American Journal of Translational Research, 2015Co-Authors: Jing Ju, Xinqun Wang, Nan Wang, Feihu ChenAbstract:Objective: This study is to investigate the in vivo effects of 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) on gastric carcinomas (GC). Methods: Adult male nude mice were subcutaneously injected with SGC-7901 human gastric cancer cells. Tumor cell cycle was analyzed with flow cytometry. The expression levels of cycloxygenase 2 (COX-2) and carcinoembryonic antigen (CEA) in xenograft tumors were detected with immunohistochemistry. The mRNA and protein expression levels of nuclear Retinoic Acid receptor β (RARβ) were detected with RT-PCR and Western blot analysis, respectively. Results: The mean survival time was dramatically increased in the ATPR treatment groups, in a dose-dependent manner. The in vivo results showed that, the xenograft tumor growth was significantly inhibited by the ATPR treatment. Moreover, the percentages of cells in the G0/G1 phase were significantly increased, while the percentages of cells in the S phase were significantly decreased, in the ATPR treatment groups. The serum levels of ALP and LDH were both dramatically decreased in the ATPR treatment groups. Furthermore, immunohistochemistry showed that, the expression levels of COX-2 and CEA were dramatically decreased in the ATPR treatment groups. Importantly, the mRNA and protein expression levels of RARβ in xenograft tumors were apparently increased by the ATPR treatment. Conclusion: ATPR could inhibit proliferation and induce differentiation of human gastric carcinoma xenografts via up-regulating RARβ expression. ATPR might be a potential effective antitumor agent for the treatment of GC.
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in vivo pharmacokinetics biodistribution and antitumor effect of amphiphilic poly l amino Acids micelles loaded with a novel all trans Retinoic Acid Derivative
European Journal of Pharmaceutical Sciences, 2014Co-Authors: Jihui Tang, Xinqun Wang, Ting Wang, Feihu Chen, Jianping ZhouAbstract:Abstract Poly(amino Acid)s are well-known as biodegradable and environmentally acceptable materials. In this study, a series of poly( l -aspartic Acid)–b-poly( l -phenylalanine) (PAA–PPA) compounds with different degrees of polymerization were used to prepare copolymer micelles for a poorly water-soluble drug 4-amino-2-trifluoromethyl-phenyl retinate (ATPR, a novel all-trans Retinoic Acid Derivative) and in vivo pharmacokinetics, biodistribution and antitumor efficacy of ATPR delivered by PAA–PPA micelles were evaluated. The area under the plasma concentration time curve AUC 0→∞ of ATPR-loaded PAA20PPA20 micelles was 2.23 and 1.97 times higher than that of ATPR solution and ATPR CrmEL solution, respectively; In addition, the mean residence time (MRT) was increased 1.67 and 1.97-fold, respectively and the total body clearance (CL) was reduced 2.25 and 1.98-fold, respectively. The biodistribution study indicated that most of the ATPR in the ATPR-M group was distributed in the liver and there was delayed liver aggregation compared with the ATPR solution and ATPR CrmEL solution groups. Furthermore, the antitumor efficacy of ATPR-loaded PAA20PPA20 micelles was demonstrated in in vivo antitumor models involving mice inoculated with the human gastric cancer cell line SGC-7901. At the same dose of 7 mg/kg, the ATPR-loaded micelles group demonstrated a better tumor growth inhibition and induced differentiation than the groups given ATPR solution and ATPR CrmEL solution. Therefore, the ATPR-loaded PAA–PPA micelles appear to be a potentially useful drug delivery system for ATPR and suitable for the chemotherapy of gastric cancer.
Soojong Um - One of the best experts on this subject based on the ideXlab platform.
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the Retinoic Acid Derivative abpn inhibits pancreatic cancer through induction of nrdp1
Carcinogenesis, 2015Co-Authors: Sanguine Byun, Seung Ho Shin, Lee Farrand, Sung Keun Jung, Soojong Um, Younja Kwon, Chengjuan Zhang, Benjamin K TsangAbstract:Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the Retinoic Acid Derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib.
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novel Retinoic Acid Derivative abpn has potent inhibitory activity on cell growth and apoptosis in cancer cells
International Journal of Cancer, 2003Co-Authors: Soojong Um, Younja Kwon, Siho Park, Jongsup ParkAbstract:Retinoids are natural and synthetic Derivatives of vitamin A that have great promise for cancer therapy and chemoprevention. Of the retinoids developed so far, 4-(N-hydroxyphenyl)retinamide (4-HPR or fenretinide) appears to have the best therapeutic potential in vitro and in vivo and is currently being tested in clinical trials for cancer prevention and therapy. To develop other potentially potent antitumor agents, we synthesized 85 retinoid Derivatives. In an initial screening of these synthetic retinoids using the HCT116 colon cancer cell line, we found that 4-amino-2-(butyrylamino)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate (ABPN or CBG41) induced the greatest growth inhibition, with an IC50 value of 0.6 μM. Subsequent studies in other cancer cell lines indicated that ABPN was much more growth-inhibitory than all-trans Retinoic Acid or 4-HPR. Compared to 4-HPR, ABPN induced 5.5- to 70.0-fold more growth inhibition in most cancer cells, with the exception of gynecologic cancer cells. In these cells, the antiproliferative effect was only 1.5- to 2.8-fold more than 4-HPR. We examined the molecular mechanism underlying the difference in growth inhibition between 4-HPR and ABPN. DAPI staining, DNA fragmentation, FACS and Western blotting analyses suggest that ABPN induced apoptosis by activating caspase-3 and -8, which may result in increased PARP cleavage. Unlike 4-HPR, ABPN activated all 3 RAR isotypes to an extent similar to AtRA. In addition, ABPN significantly inhibited AP-1 transcriptional activity and thus greatly suppressed the expression of the matrix metalloproteinase -1, -2 and -3 genes, which are involved in tumor invasion. These results suggest that ABPN may be a promising retinoid Derivative offering not only enhanced cytotoxicity, but also increased inhibition of tumor invasiveness. © 2003 Wiley-Liss, Inc.
Eric I C Li - One of the best experts on this subject based on the ideXlab platform.
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inhibition of transforming growth factor β induced liver fibrosis by a Retinoic Acid Derivative via the suppression of col 1a2 promoter activity
Biochemical and Biophysical Research Communications, 2008Co-Authors: Kun Lin Yang, Wenteng Chang, Kuo Chen Hung, Eric I C Li, Chia Chang ChuangAbstract:: Transforming growth factor-beta1 (TGF-beta1) mediates expression of collagen 1A2 (Col 1A2) gene via a synergistic cooperation between Smad2/Smad3 and Sp1, both act on the Col 1A2 gene promoter. In our previous study, we reported that a Retinoic Acid Derivative obtained from Phellinus linteus (designated PL) antagonizes TGF-beta-induced liver fibrosis through regulation of ROS and calcium influx. In this continuing study we seek further the effect of PL on the Smad signaling pathway. We used a Col 1A2 promoter-luciferase construct to study the action of PL on Smad through TGF-beta. We found that PL decreases the promoter activity of Col 1A2, hinders the translocalization of phosphorylated Smad2/3-Smad 4 complex from cytosol into nucleus and inhibits Sp1 binding activity. These results suggest that PL inhibits TGF-beta1-induced Col 1A2 promoter activity through blocking ROS and calcium influx as well as impeding Sp1 binding and translocalization of pSmad 2/3-Smad4 complex into nucleus.
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antagonizing tgf β induced liver fibrosis by a Retinoic Acid Derivative through regulation of ros and calcium influx
Biochemical and Biophysical Research Communications, 2008Co-Authors: Kun Lin Yang, Wenteng Chang, Chia Chang Chuang, Kuo Chen Hung, Eric I C LiAbstract:Abstract Transforming growth factor-beta1 (TGF-β1) mediates the regulation of extracellular matrix via reactive oxygen species (ROS) and calcium influx, both are activators of hepatic stellate cells (HSC) which play a critical role in hepatic fibrogenesis. Hence one can use ROS assay as the main screening tool for molecules that might antagonize the process of liver fibrosis. A Retinoic Acid Derivative isolated from the mycelium of Phellinus linteus that down-regulates ROS generation and calcium influx in HSC-T6 cells was thus obtained in our screening process. The Retinoic Acid Derivative also reverses an early liver fibrosis, as assayed by liver contents of hydroxyproline, α-smooth muscle actin (α-SMA), and collagen 1A2, in an early liver fibrosis model we established previously where an inducible expression vector containing a TGF-β gene was hydrodynamically transferred into a testing animal. Retinoic Acid Derivative thus acts both in vitro and in vivo to prevent liver fibrosis at an early phase.
Sanguine Byun - One of the best experts on this subject based on the ideXlab platform.
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the Retinoic Acid Derivative abpn inhibits pancreatic cancer through induction of nrdp1
Carcinogenesis, 2015Co-Authors: Sanguine Byun, Seung Ho Shin, Lee Farrand, Sung Keun Jung, Soojong Um, Younja Kwon, Chengjuan Zhang, Benjamin K TsangAbstract:Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the Retinoic Acid Derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib.
Vincent C O Njar - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 340 inhibition of autophagy enhances the anticancer activity of the Retinoic Acid Derivative vn 12 1 in endocrine resistant human breast cancer cell lines
Cancer Research, 2010Co-Authors: Abhijit M Godbole, Puranik Purushottamachar, Lalji K Gediya, Vincent C O NjarAbstract:Breast cancer is the most common cancer and the second leading cause of cancer related deaths among women in the United States. Although endocrine therapies such as anti-estrogens and aromatase inhibitors have improved the overall survival, resistance to this therapy remains a major concern. Autophagy is a unique, regulated mechanism of cell survival by catabolism of proteins under nutrient deprivation or chemotherapeutic stress. It is an important cause of resistance to chemotherapeutic agents. VN/12-1, a novel 4-imidazolyl methyl ester of Retinoic Acid synthesized in our laboratory, showed excellent anti-proliferative activity (as shown by MTT assay) in endocrine resistant human breast cancer cell lines SK-BR-3 and MDA-MB-231. Its IC 50 in SK-BR-3 cells was 5.2 μ M compared to 15.2 μ M (all-trans Retinoic Acid-ATRA) and 45.6 μ M (letrozole). For MDA-MB-231 cells, IC 50 of VN/12-1 was 7.3 μ M compared to 53.7 μ M (ATRA) and 74.3 μ M (letrozole). At low micromolar concentrations of VN/12-1 treatment on these cells, western blot analysis and imaging studies confirmed the presence of autophagosomes. This was associated with up-regulation of proteins involved in endoplasmic reticulum (ER) stress, markers for DNA damage and downregulation of cyclin D1 and phosphorylated Akt. Co-treatment with chloroquine (an autophagy inhibitor) resulted in increased sensitivity of cells to VN/12-1 as indicated by decrease in cell viability from 71.22% for VN/12-1 (3 μM) alone, 90.18% chloroquine (3 μM) alone to 34.31% for the combination of VN/12-1 (3 μM) and chloroquine (3 μM) in SK-BR-3 cells. It also resulted in induction of apoptosis which was caspase mediated. In summary, ER stress and DNA damage induced by VN/12-1 resulted in cell cycle arrest and induction of autophagy. Inhibition of autophagy by chloroquine overwhelmed this cellular stress and resulted in apoptotic cell death in endocrine resistant breast cancer cell lines. Significance: VN/12-1 and its combination with autophagy inhibitor chloroquine is a novel therapeutic alternative to treat endocrine resistant breast cancer and hence warrants further pre-clinical and clinical development. This is the first in vitro study which showed an enhancement of anti-cancer activity of a Retinoic Acid Derivative by an autophagy inhibitor in endocrine resistant human breast cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-340.
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Abstract LB-340: Inhibition of autophagy enhances the anticancer activity of the Retinoic Acid Derivative VN/12-1 in endocrine resistant human breast cancer cell lines
Cancer Research, 2010Co-Authors: Abhijit M Godbole, Puranik Purushottamachar, Lalji K Gediya, Vincent C O NjarAbstract:Breast cancer is the most common cancer and the second leading cause of cancer related deaths among women in the United States. Although endocrine therapies such as anti-estrogens and aromatase inhibitors have improved the overall survival, resistance to this therapy remains a major concern. Autophagy is a unique, regulated mechanism of cell survival by catabolism of proteins under nutrient deprivation or chemotherapeutic stress. It is an important cause of resistance to chemotherapeutic agents. VN/12-1, a novel 4-imidazolyl methyl ester of Retinoic Acid synthesized in our laboratory, showed excellent anti-proliferative activity (as shown by MTT assay) in endocrine resistant human breast cancer cell lines SK-BR-3 and MDA-MB-231. Its IC 50 in SK-BR-3 cells was 5.2 μ M compared to 15.2 μ M (all-trans Retinoic Acid-ATRA) and 45.6 μ M (letrozole). For MDA-MB-231 cells, IC 50 of VN/12-1 was 7.3 μ M compared to 53.7 μ M (ATRA) and 74.3 μ M (letrozole). At low micromolar concentrations of VN/12-1 treatment on these cells, western blot analysis and imaging studies confirmed the presence of autophagosomes. This was associated with up-regulation of proteins involved in endoplasmic reticulum (ER) stress, markers for DNA damage and downregulation of cyclin D1 and phosphorylated Akt. Co-treatment with chloroquine (an autophagy inhibitor) resulted in increased sensitivity of cells to VN/12-1 as indicated by decrease in cell viability from 71.22% for VN/12-1 (3 μM) alone, 90.18% chloroquine (3 μM) alone to 34.31% for the combination of VN/12-1 (3 μM) and chloroquine (3 μM) in SK-BR-3 cells. It also resulted in induction of apoptosis which was caspase mediated. In summary, ER stress and DNA damage induced by VN/12-1 resulted in cell cycle arrest and induction of autophagy. Inhibition of autophagy by chloroquine overwhelmed this cellular stress and resulted in apoptotic cell death in endocrine resistant breast cancer cell lines. Significance: VN/12-1 and its combination with autophagy inhibitor chloroquine is a novel therapeutic alternative to treat endocrine resistant breast cancer and hence warrants further pre-clinical and clinical development. This is the first in vitro study which showed an enhancement of anti-cancer activity of a Retinoic Acid Derivative by an autophagy inhibitor in endocrine resistant human breast cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-340.