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Stern L, Giese N, Hackert T, Strobel O, Schirmacher P, Felix K, Gaida MM. Overcoming chemoresistance in pancreatic cancer cells: role of the bitter taste receptor T2R10. J Cancer 2018; 9:711-725. [PMID: 29556329 PMCID: PMC5858493 DOI: 10.7150/jca.21803] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 11/26/2017] [Indexed: 12/14/2022] Open
Abstract
Bitter taste receptors (T2Rs) are G-protein coupled transmembrane proteins initially identified in the gustatory system as sensors for the taste of bitter. Recent evidence on expression of these receptors outside gustatory tissues suggested alternative functions, and there is growing interest of their potential role in cancer biology. In this study, we report for the first time, expression and functionality of the bitter receptor family member T2R10 in both human pancreatic ductal adenocarcinoma (PDAC) tissue and PDAC derived cell lines. Caffeine, a known ligand for T2R10, rendered the tumor cells more susceptible to two standard chemotherapeutics, Gemcitabine and 5-Fluoruracil. Knocking down T2R10 in the cell line BxPC-3 reduced the caffeine-induced effect. As possible underlying mechanism, we found that caffeine via triggering T2R10 inhibited Akt phosphorylation and subsequently downregulated expression of ABCG2, the so-called multi-drug resistance protein that participates in rendering cells resistant to a variety of chemotherapeutics. In conclusion, T2R10 is expressed in pancreatic cancer and it downmodulates the chemoresistance of the tumor cells.
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Affiliation(s)
- Louisa Stern
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalia Giese
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Klaus Felix
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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Epigallocatechin-3-Gallate: The Prospective Targeting of Cancer Stem Cells and Preventing Metastasis of Chemically-Induced Mammary Cancer in Rats. Am J Med Sci 2017; 354:54-63. [DOI: 10.1016/j.amjms.2017.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 02/11/2017] [Accepted: 03/01/2017] [Indexed: 01/11/2023]
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Li C, Sun BQ, Gai XD. Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours. Clin Transl Oncol 2014; 16:593-8. [PMID: 24643703 DOI: 10.1007/s12094-014-1169-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 02/19/2014] [Indexed: 12/13/2022]
Abstract
Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One of the main underlying mechanisms of this resistance is the over-expression of P-glycoprotein (P-gp), an ATP-dependent transmembrane transporter protein encoded by the MDR1 gene. P-gp might transport anti-cancer drugs out of cancer cells and decrease effective intracellular drug concentrations. An effective approach to overcome MDR is to inhibit the function of P-gp or its expression on the surface of cancer cells. Thus, application of MDR reversal agents can be seen as a potentially important means by which to overcome the clinical drug resistance of tumour cells and improve the efficacy of chemotherapy. Recently, research efforts worldwide have focused on reversal mechanisms for MDR and on the identification of reversal agents. Chinese scholars have performed a great deal of exploratory work by screening for efficacy and low toxicity in drug resistance reversal compounds. These compounds may provide more lead compounds with greater activity, leading to the development of more effective therapies for MDR cancer cells. In this review, the function and efficiency of novel compounds derived from traditional Chinese medicines are described.
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Affiliation(s)
- C Li
- Department of Pathology, School of Basic Medical Sciences, Beihua University, 3999 Huashan Road, Jilin, 132013, People's Republic of China
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Vinod BS, Maliekal TT, Anto RJ. Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance. Antioxid Redox Signal 2013; 18:1307-48. [PMID: 22871022 DOI: 10.1089/ars.2012.4573] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.
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Affiliation(s)
- Balachandran S Vinod
- Cancer Research Program, Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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Granados-Principal S, Quiles JL, Ramirez-Tortosa CL, Sanchez-Rovira P, Ramirez-Tortosa MC. New advances in molecular mechanisms and the prevention of adriamycin toxicity by antioxidant nutrients. Food Chem Toxicol 2010; 48:1425-38. [PMID: 20385199 DOI: 10.1016/j.fct.2010.04.007] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 03/29/2010] [Accepted: 04/06/2010] [Indexed: 12/29/2022]
Abstract
Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are currently the most effective group of anti-neoplastic drugs used in clinical practice. Of these, doxorubicin (also called adriamycin) is a key chemotherapeutic agent in cancer treatment, although its use is limited as a consequence of the chronic and acute toxicity associated with this drug. The molecular mechanisms of doxorubicin account for both the anti-cancer and the toxic side effects. Many antioxidants have been assayed, with positive or negative results, to prevent the toxicity of doxorubicin. The present review has two main goals: (1) to report the latest findings regarding the molecular mechanisms of doxorubicin toxicity; (2) to update our understanding of the role of natural antioxidants in preventive therapy against doxorubicin-induced toxicity. This review provides new evidence for the chemoprevention of doxorubicin toxicity, making use of natural antioxidants - in particular vitamin E, vitamin C, coenzyme Q, carotenoids, vitamin A, flavonoids, polyphenol, resveratrol, antioxidant from virgin olive oil and selenium - and offers new insights into the molecular mechanisms of doxorubicin toxicity with respect to DNA damage, free radicals and other parameters.
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Affiliation(s)
- Sergio Granados-Principal
- Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology José Mataix Verdú, University of Granada, Granada, Spain
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Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol 2005; 56:1307-14. [PMID: 15482646 DOI: 10.1211/0022357044364] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The aim of this study was to examine the effect and mechanism of green tea polyphenols (TP) on reversal of multidrug resistance (MDR) in a carcinoma cell line. Using the MTT assay, TP was examined for its modulating effects on the drug-resistant KB-A-1 cells and drug-sensitive KB-3-1 cells. When 10 microg mL(-1) (-)-epigallocatechin gallate (EGCG) or 40 microg mL(-1) TP were present simultaneously with doxorubicin (DOX), the IC50 of DOX on KB-A-1 cells decreased from 10.3 +/- 0.9 microg mL(-1) to 4.2 +/- 0.2 and 2.0 +/- 0.1 microg mL(-1), respectively. TP and EGCG enhanced the DOX cytotoxicity on KB-A-1 cells by 5.2- and 2.5-times, respectively, but did not show a modulating effect on KB-3-1 cells. This indicated that both TP and EGCG had reversal effects on the MDR phenotype in-vitro. A KB-A-1 cell xenograft model was established, and the effect of TP on reversing MDR in-vivo was determined. Mechanistic experiments were conducted to examine the uptake, efflux and accumulation of DOX. Cloning and expression of the nucleotide binding domain of the human MDR1 gene in Escherichia coli was established, and by using colorimetry to examine the activity of ATPase to hydrolyse ATP, the ATPase activity of target nucleotide binding domain protein was determined. TP exerted its reversal effects through the inhibition of ATPase activity, influencing the function of P-glycoprotein, and causing a decreased extrusion of anticancer drug and an increased accumulation of anticancer drug in drug resistant cells. Using reverse transcription-polymerase chain reaction, the inhibitory effect of TP on MDR1 gene expression was investigated. Down-regulation of MDR1 gene expression was the main effect, which resulted in the reversal effect of TP on the MDR phenotype. TP is a potent MDR modulator with potential in the treatment of P-glycoprotein mediated MDR cancers.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Adenosine Triphosphatases/antagonists & inhibitors
- Adenosine Triphosphatases/metabolism
- Animals
- Antibiotics, Antineoplastic/pharmacokinetics
- Antibiotics, Antineoplastic/pharmacology
- Catechin/analogs & derivatives
- Catechin/metabolism
- Catechin/pharmacology
- Cell Line, Tumor
- Doxorubicin/pharmacokinetics
- Doxorubicin/pharmacology
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Multiple/genetics
- Drug Resistance, Neoplasm/drug effects
- Escherichia coli/genetics
- Escherichia coli/metabolism
- Flavonoids/metabolism
- Flavonoids/pharmacology
- Gene Expression Regulation
- Genes, MDR/genetics
- Genes, MDR/physiology
- Genetic Therapy
- Humans
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Phenols/metabolism
- Phenols/pharmacology
- Polyphenols
- Tea/chemistry
- Transformation, Bacterial
- Transplantation, Heterologous
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Affiliation(s)
- Yuying Mei
- Department of Molecular and Cellular Biochemistry, 240 Combs building, Chandler Medical Center, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA.
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Zhang Q, Wei D, Liu J. In vivo reversal of doxorubicin resistance by (−)-epigallocatechin gallate in a solid human carcinoma xenograft. Cancer Lett 2004; 208:179-86. [PMID: 15142676 DOI: 10.1016/j.canlet.2004.01.033] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2003] [Revised: 01/27/2004] [Accepted: 01/28/2004] [Indexed: 11/20/2022]
Abstract
A human carcinoma xenograft model was established with resistant KB-A-1 cell line in order to investigate whether (-)-epigallocatechin gallte (EGCG) can reverse doxorubicin (DOX) resistance in vivo. EGCG could sensitize the tumors to DOX as indicated by a considerable reduction of tumor weights. The combination of DOX with EGCG increased the DOX concentration by 51% in the tumors, and increased DOX-induced apoptosis in the tumors compared with DOX alone. In addition, the combination schedules appeared to be well tolerated. We conclude that EGCG could chemosensitize resistant tumor cells to DOX in vivo through an increase in the accumulation of DOX in the tumors.
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Affiliation(s)
- Qiang Zhang
- State Key Laboratory of Bioreactor Engineering, New World Institute of Biotechnology, East China University of Science and Technology, Shanghai 200237, People's Republic of China
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Liu TT, Liang NS, Li Y, Yang F, Lu Y, Meng ZQ, Zhang LS. Effects of long-term tea polyphenols consumption on hepatic microsomal drug-metabolizing enzymes and liver function in Wistar rats. World J Gastroenterol 2003; 9:2742-4. [PMID: 14669325 PMCID: PMC4612044 DOI: 10.3748/wjg.v9.i12.2742] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of long-term tea polyphenols (TPs) consumption on hepatic microsomal drug-metabolizing enzymes and liver function in rats.
METHODS: TPs were administered intragastrically to rats at the doses of 833 mg·kg-1·d–1 (n = 20) and 83.3 mg·kg-1·d-1 (n = 20) respectively for six months. Controlled group (n = 20) was given same volume of saline solution. Then the contents of cytochrome P450, b5, enzyme activities of aminopyrine N-demethylase (ADM), glutathione S-trasferase (GST) and the biochemical liver function of serum were determined.
RESULTS: The contents of cytochrome P450 and b5 in the livers of male rats in high dose groups (respectively 2.66 ± 0.55, 10.43 ± 2.78 nmol·mg MS pro-1) were significantly increased compared with the control group (1.08 ± 1.04, 5.51 ± 2.98 nmol·mg MS pro- 1; P < 0.01, respectively). The enzymatic activities of ADM in the livers of female rats in high dose groups (0.91 ± 0.08 mmol·mg MS pro-1min-1) were increased compared with the control group (0.82 ± 0.08 mmol·mg MS pro-1·min-1; P < 0.05). The GST activity was unchanged in all treated groups, and the function of liver was not obviously changed.
CONCLUSION: The antidotal capability of rats’ livers can be significantly improved after long-term consumption of TPs. There are differences in changes of drug-metabolizing enzymes between the sexes induced by TPs and normal condition.
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Affiliation(s)
- Tao-Tao Liu
- Department of Pharmacy, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
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