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1.
J Ethnopharmacol ; 261: 113118, 2020 Oct 28.
Article in English | MEDLINE | ID: mdl-32621953

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Green tea is the most ancient and popular beverage worldwide and its main constituent epigallocatechin-3-gallate (EGCG) has a potential role in the management of cancer through the modulation of cell signaling pathways. However, EGCG is frangible to oxidation and exhibits low lipid solubility and bioavailability, and we synthesized a derivative of EGCG in an attempt to overcome these limitations. AIM OF THE STUDY: The anthracycline antibiotic daunorubicin (DNR) is a potent anticancer agent. However, its severe cardiotoxic limits its clinical efficacy. Human carbonyl reductase 1 (CBR1) is one of the most effective human reductases for producing hydroxyl metabolites and thus may be involved in increasing the cardiotoxicity and decreasing the antineoplastic effect of anthracycline antibiotics. Accordingly, in this study, we investigated the co-therapeutic effect of Y6, a novel and potent adjuvant obtained by optimization of the structure of EGCG. MATERIAL AND METHODS: The cellular concentrations of DNR and its metabolite DNRol were measured by HPLC to determine the effects of EGCG and Y6 on the inhibition of DNRol formation. The cytotoxic effects of EGCG and Y6 were tested by MTT assay in order to identify non-toxic concentrations of them. To understand their antitumor and cardioprotective mechanisms, hypoxia-inducible factor-1α (HIF-1α) and CBR1 protein expression was measured via Western blotting and immunohistochemical staining while gene expression was analyzed using RT-PCR. Moreover, PI3K/AKT and MEK/ERK signaling pathways were analyzed via Western blotting. HepG2 xenograft model was used to detect the effects of EGCG and Y6 on the antitumor activity and cardiotoxicity of DNR in vivo. Finally, to obtain further insight into the interactions of Y6 and EGCG with HIF-1α and CBR1, we performed a molecular modeling. RESULTS: Y6(10 µg/ml or 55 mg/kg) decreased the expression of HIF-1α and CBR1 at both the mRNA and protein levels during combined drug therapy in vitro as well as in vivo, thereby inhibiting formation of the metabolite DNRol from DNR, with the mechanisms being related to PI3K/AKT and MEK/ERK signaling inhibition. In a human carcinoma xenograft model established with subcutaneous HepG2 cells, Y6(55 mg/kg) enhanced the antitumor effect and reduced the cardiotoxicity of DNR more effectively than EGCG(40 mg/kg). CONCLUSIONS: Y6 has the ability to inhibit CBR1 expression through the coordinate inhibition of PI3K/AKT and MEK/ERK signaling, then synergistically enhances the antitumor effect and reduces the cardiotoxicity of DNR.


Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Arrhythmias, Cardiac/prevention & control , Carcinoma, Hepatocellular/drug therapy , Catechin/analogs & derivatives , Daunorubicin/pharmacology , Enzyme Inhibitors/pharmacology , Liver Neoplasms/drug therapy , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Animals , Antibiotics, Antineoplastic/toxicity , Antineoplastic Combined Chemotherapy Protocols/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/physiopathology , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cardiotoxicity , Catechin/pharmacology , Cell Proliferation/drug effects , Daunorubicin/toxicity , Drug Synergism , Female , Gene Expression Regulation, Neoplastic , Heart Rate/drug effects , Hep G2 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/enzymology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Nude , Signal Transduction , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
2.
J Ethnopharmacol ; 259: 112852, 2020 Sep 15.
Article in English | MEDLINE | ID: mdl-32278759

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Hypervascularity has been considered as one of the major features of many solid tumors. Green tea is one of the commonly drink resources in China, and its active component, Epigallocatechin gallate (EGCG), exhibits antiangiogenic activities in various experimental tumor models. However, EGCG has many shortages, e.g., relatively unstable, low lipid solubility, poor bioavailability, and short duration of action. AIM OF THE STUDY: To overcome the shortages of EGCG for antiangiogenic antitumor usage, our study developed a novel EGCG derivate, Y6(5,3',4',3″,4″,5″-6-0-ethyl-EGCG). The underlying mechanism was also elucidated. MATERIAL AND METHODS: we evaluated the effects of EGCG, Y6 on HCC and angiogenesis in vivo and in vitro. Moreover, to understand their antitumor mechanisms, key factors within angiogenesis-related signaling pathways (MAPK/ERK1/2, PI3K/AKT, HIF-1 VEGF) were analyzed by using western blot, immunohistochemistry (IHC), quantitative real-time quantitative PCR (RT-PCR). HepG2 xenograft model and the chorioallantoic membrane (CAM) were used to investigate the effects of Y6 and EGCG on tumors and anti-angiogenesis in vivo. Micro-vessel density (MVD) was analyzed by IHC of CD34 staining. IHC, qRT-PCR and Western blot were used to detect the expression of HIF-1α and VEGF protein in tumor tissues. The protein levels of MAPK/ERK1/2, PI3K/AKT, HIF-1α, and VEGF in tumor tissues were detected by western blot. RESULTS: Our results demonstrated that both EGCG and Y6 displayed antiangiogenetic and antitumor effects against HCC cells in vitro and in vivo. We found that rather than equal amount of EGCG, Y6 displayed better abilities in inhibiting the growth of HCC tumor cells, as well as inhibiting the growth of neovascularization in the chick embryos and HepG2 xenograft tumors bearing-mice, based on the data obtained from MTT assay, immunohistochemistry (IHC), chick chorioallantoic membrane (CAM) assays. In the comparison of equivalent dose of EGCG, qRT-PCR data showed that Y6 induced more significant decrease of the mRNA levels of HIF-1α and VEGF in supernatant-treated SMMC-7721 cells under hypoxic condition, as well as in the in xenograft tumor tissues; whereas Y6 also significantly reduced the protein levels of MAPK/ERK1/2, PI3K/AKT, HIF-1α, and VEGF to a greater extent than EGCG, determined by western blotting assay. CONCLUSIONS: our work suggests that the new EGCG derivate Y6 could significantly inhibit tumor growth and angiogenesis which is possibly involved with the signaling intervention of MAPK/ERK1/2 and PI3K/AKT/HIF-1α/VEGF pathways, and is supposed to be a potential therapeutic reagent for anti-angiogenesis treatment of solid tumors.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Carcinoma, Hepatocellular/drug therapy , Catechin/analogs & derivatives , Liver Neoplasms/drug therapy , MAP Kinase Signaling System/drug effects , Animals , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/metabolism , Catechin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chick Embryo , Chorioallantoic Membrane/pathology , Hep G2 Cells , Human Umbilical Vein Endothelial Cells , Humans , Liver Neoplasms/blood supply , Liver Neoplasms/metabolism , Mice , Mitogen-Activated Protein Kinase Kinases/metabolism , Neovascularization, Pathologic/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor Assays
3.
Oncotarget ; 8(18): 29760-29770, 2017 May 02.
Article in English | MEDLINE | ID: mdl-28423656

ABSTRACT

Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y6, a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y6. Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y6, as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.


Subject(s)
Antineoplastic Agents/pharmacology , Catechin/analogs & derivatives , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Apoptosis/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Catechin/chemistry , Catechin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Gene Expression , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism
4.
Chinese Medical Journal ; (24): 2874-2878, 2011.
Article in English | WPRIM (Western Pacific) | ID: wpr-292786

ABSTRACT

<p><b>BACKGROUND</b>The common γ chain (γc) plays a critical role in regulating proliferation, differentiation, and apoptosis of peripheral T-cells. It was previously confirmed that blocking the γc signal can successfully induce transplant tolerance in a murine model. Here we investigated the potential mechanism.</p><p><b>METHODS</b>Splenocytes from C57BL/6 mice were transfused into T-cell deficient Balb/c nude mice that were reconstituted with syngeneic wild-type T-cells labeled with 5-carboxyfluorescein diacetate succinimidyl ester (CFSE). After 24 hours, recipients received i.p. injection of mixture of anti-γc mAbs, or with isotype control IgG2a. The labeled T-cells were harvested from recipient spleens after 12 and 48 hours. T-cell proliferation and apoptosis were detected by flow cytometry.</p><p><b>RESULTS</b>T-cell proliferation was markedly inhibited and apoptotic T cells could be detected at 12 hours after the mAbs injection. Proliferation was inhibited at 48 hours, but the proportion of apoptotic T-cells was not more than at 12 hours. In the control group, however, T-cells actively proliferated and no significant apoptosis was detected at either time point.</p><p><b>CONCLUSIONS</b>The results suggested that blockade of γc signals can synergize with donor splenocyte transfusion and lead to inhibition of antigen-specific T-cell proliferation and induction of apoptotic T-cell death. This protocol may develop a novel approach to induce donor-specific tolerance.</p>


Subject(s)
Animals , Male , Mice , Antibodies, Monoclonal , Pharmacology , Apoptosis , Cells, Cultured , Flow Cytometry , Fluoresceins , Immune Tolerance , Interleukin Receptor Common gamma Subunit , Metabolism , Lymphocyte Activation , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Signal Transduction , Spleen , Cell Biology , Succinimides , T-Lymphocytes , Cell Biology
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