臺灣博碩士論文加值系統

研究背景:利用抗癌藥物治療乳癌患者是臨床上最主要治療的方法之一，像是歐洲紫杉醇(Docetaxel)和阿黴素(Doxorubicin)都是臨床上認證有效的抗癌藥物，其作用於阻擋癌細胞進行快速分裂，但針對體內正常細胞或組織同時也會受到抗癌藥物的影響而對人體帶來強大的副作用。先前研究與臨床上發現，治療癌症患者通常無法持久且有效發揮療效的原因來自於癌細胞對於抗癌藥物產生多重抗藥性；藉由ATP活化的作用，使藥物幫浦蛋白表現量增加，導致將抗癌藥物排出到癌細胞外，因此真正進入到癌細胞內的抗癌藥物濃度降低而產生無法有效毒殺癌細胞的結果。研究中利用一具備有能力抑制多重抗藥性產生的藥物結合抗癌藥物作為合併治療，而為了降低藥物對體內造成的毒性，將合併治療藥物包覆於高生物相容性且無毒安全的載體中，藉由高滲透長滯留效應(EPR effect)將載體運輸至腫瘤達成治療的效果。

研究目的:本研究利用具有抑制抗藥性的藥物結合抗癌藥物的合併治療為設計概念，降低治療對人體產生的副作用、避免抗藥性的產生，進而增加治療之療效。

材料與方法:2, 3, 5, 4‘-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG)為從何首烏中萃取出的活性成分，T1為其衍生物，實驗中所結合使用的抗癌藥物為歐洲紫杉醇(Docetaxel, DTX)和阿黴素(Doxorubicin, DOX)，進行細胞實驗觀察其治療效果並且利用藥物合併指數(CI值)以評估此藥物合併治療是否具備協同效應，此外，我們亦利用西方墨點法(Western blotting)實驗發現其衍生物(T1)具有抑制抗藥性幫浦的能力。微脂體為實驗中所使用的安全性載體，藉由薄膜水合法製備出包覆藥物的微脂體，動物實驗中利用微脂體的特性與高滯留長效應(EPR effect)使其滯留於腫瘤附近的區域，進而分析此合併治療是否能有效對抗腫瘤的生長。

結果:實驗結果顯示，以T1與抗癌藥物進行合併治療能促進藥物毒殺癌細胞的效果，並且於藥物合併指數上亦具有強烈的協同作用；抗藥性實驗結果指出，抗癌藥物會刺激藥物幫浦的蛋白量提升。當加入T1後，能夠抑制P-gp和BCRP藥物幫浦的蛋白表現量，以此特性證明其有能力調控功能性基因的表現，證實T1具有能抑制多重抗藥性的能力。 由於DTX與T1以莫耳濃度1:3的比例下之藥物合併指數(CI值)小於0.2，相較於DOX的合併使用，具有更強烈的協同效應，因此將其包覆於微脂體中，所製備出的粒徑大小為113.8 ± 2.8 nm，DTX與T1包覆率分別為78.55 ± 1.7 %與15.75 ± 0.16 %，動物實驗中也證明了當合併治療藥物中的DTX減低75%劑量，能保持對於腫瘤的療效，也意味著對於抗癌藥物對於體內的毒性能降低。

結語:本篇研究指出T1與抗癌藥物作為合併治療藉由抑制P-gp與BCRP的活性來增加抗癌藥物的療效，動物實驗中也證實了此藥物合併治療能同時具有療效及減低抗癌藥物所帶來的副作用，因此，藥物合併治療對於乳癌病患及具有抗藥性之患者而言都具有臨床應用上的潛能，期望未來能促進抗癌藥物的發展與改善現今癌症化療藥物治療上所面臨的困境。

Background: Chemotherapy used by anticancer drugs for treating breast cancer is the main treatment in clinical application, for instance, docetaxel and doxorubicin, the highly effective anticancer drugs, which have the abilities of blocking the rapid cell divisions for cancer cells; however, they also influence the normal cells or tissues, leading to emerge severe side effect for the patients. Previous studies and clinic applications found that the reason of the anticancer drugs couldn’t use effectively for long-term therapy was mainly due to multidrug resistance (MDR) generated from cancer cells against the anticancer drugs. In this study, we constructed the combination therapy of anticancer drug and a novel derivative, T1, which was capable of inhibiting MDR. In order to decrease the toxicity which drugs brought to the bodies, utilizing the safe, biocompatible, non-toxic carrier encapsulate drugs for the treatment. Moreover, the carrier could bring the drugs to the tumor region by enhanced permeability and retention effect (EPR effect).

Aim: To improve the long-term therapeutic effect and overcome MDR, we developed novel strategies to solve the difficulties. One was the combination therapy of anticancer drugs and a novel derivative, T1, and the other one was utilizing drug carriers encapsulating drugs, such as liposomes to promote the efficacy.

Materials and Methods: T1 was a derivative from 2, 3, 5, 4‘-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG). Cytotoxicity of anticancer drugs and T1 was analyzed by MTT assay. Combination index (CI) was calculated to evaluate whether the combination therapy had synergism or not. To investigate MDR, we examined the expressions of ATP-binding cassette transporters, including P-gp, MRP1, and BCRP by western blotting analysis. In this study, liposome was used and it was fabricated by thin-film hydration. In animal study, we utilized the property of liposomes and EPR effect to let them accumulate at the tumor region for the further analysis of anti-tumor effect.

Results: The results showed that the combination therapy could enhance the cytotoxicity against cancer cells and had a strong synergism by calculating combination index (CI). Moreover, concentrations of anticancer drugs could be decreased as combined with T1, which might cut down the severe side effect. The experiments of MDR analyzed by western blotting indicated that the anticancer drugs would cause the overexpression of the drug efflux pump proteins, whereas P-gp and BCRP expressions would be downregulated after T1 added. Because CI value of DTX combined with T1 in the molar ratio of 1:3 was less than 0.2, which meant it had the stronger synergism than DOX combined with T1, encapsulating DTX and T1 into liposomes for the further experiments. The size of liposomes was 113.3 ± 2.8 nm and the encapsulation efficiencies of DTX and T1 were 78.55 ± 1.7 % and 15.75 ± 0.16 % respectively. In animal study, it also indicated that the combination therapy was effective; furthermore, as the dose of DTX was reduced to 75%, it still remained the anti-tumor effect, which might decrease the toxicity of anticancer drugs.

Conclusion: This study proved that the combinational therapy of anticancer drugs and T1 could increase the cytotoxicity via suppressing the activity of P-gp and BCRP efflux pump. Animal study also revealed this combinational therapy had the therapeutic effect and might have the high possibility to decrease side effect of anticancer drugs at the same time. Therefore, it might have the potential used in clinic for breast cancer patients and those with MDR.

Abbreviations.....I
摘要.....II
Abstract.....IV
Chapter 1: Introduction.....1
1.1 Breast cancer.....1
1.2 Chemotherapy for breast cancer treatment.....1
1.2.1 Taxanes.....2
1.2.2 Doxorubicin.....4
1.3 Multidrug resistance (MDR).....5
1.3.1 ATP-binding cassette transporters (ABC transporters).....6
1.3.1.1 P-glycoprotein (P-gp).....8
1.3.1.2 Multidrug resistance-associated protein 1 (MRP1).....9
1.3.1.3 Breast cancer resistance protein (BCRP).....9
1.4 Chemosensizers.....10
1.4.1 Resveratrol (3,5,4''-trihydroxy-trans-stilbene).....10
1.4.2 A novel derivative of THSG (2, 3, 5, 4''- tetrahydroxystilbene- 2- O- beta- D- glucoside), T1.....11
1.5 Drug carriers system.....12
1.5.1 Liposomes.....12
1.5.1.1 Classifications.....13
1.5.1.2 Preparations.....13
1.5.1.3 Functions and applications.....14
1.5.1.4 Intracellular interactions.....15
Chapter 2: Aim of the study.....16
Chapter 3: Materials and Methods.....17
3.1 Flow chart of the study.....17
3.2 Experimental materials, drugs and reagents.....18
3.3 Experimental instruments.....21
3.4 Cell culture in vitro.....22
3.4.1 Cell viability.....22
3.4.2 Assessment of drug combination synergism and combination index.....23
3.5 Specific protein expression analysis.....24
3.5.1 Western blotting......24
3.5.1.1 Sample preparation.....24
3.5.1.2 Quantification proteins by Bio-RAD Protein Assay.....24
3.5.1.3 Protein separation by gel electrophoresis.....25
3.5.1.4 Transferring protein from gel to membrane.....25
3.5.1.5 Antibody incubation.....26
3.5.1.6 Imaging and data analysis.....26
3.5.2 Fluorescence staining.....27
3.6 Liposome preparation.....28
3.6.1 Characterization of liposomes.....29
3.6.2 Drug loading (DL) and encapsulation efficiency (EE).....29
3.6.2.1 Encapsulation efficiency of docetaxel in liposomes.....30
3.6.2.2 Encapsulation efficiency of T1 in liposomes.....30
3.7 In vivo anti-tumor effect....31
3.8 Statistical analysis.....32
Chapter 4: Results.....33
4.1 Evaluation the effect of the anticancer drugs and the chemosensizers on human breast cancer cell lines.....33
4.1.1 Cell viability assay.....33
4.1.2 Calculating Combination index for drug synergism.....35
4.2 Multidrug resistance analysis.....36
4.2.1 Western blotting.....36
4.2.2 Fluorescence images.....37
4.3 Characterization of liposomal formulation.....38
4.3.1 Particle size and its distribution of liposomal formulation.....38
4.3.2 Drug loading and encapsulation efficiency in liposomes.....38
4.4 In vivo anti-tumor effect.....39
Chapter 5: Discussions.....41
Chapter 6: Conclusions.....45
References.....66

Contents of figures and tables
Figure 1: Chemical structure of paclitaxel.....3
Figure 2: Chemical structure of docetaxel.....3
Figure 3: Chemical structure of doxorubicin.....4
Figure 4: Multiple mechanisms of multidrug resistance.....5
Figure 5: Schematic diagram of ATP-binding cassette transporters.....7
Figure 6: Structure of P-gp, MRP1, and BCRP.....9
Figure 7: Chemical structure of Resveratrol.....10
Figure 8: Chemical structure of THSG.....11
Figure 9: Illustration of the study.....16
Figure 10: Flow chart of the study.....17
Figure 11: Illustration of liposome extruder.....29
Figure 12: Cell viability of anticancer drugs in breast cancer cells.....46
Figure 13: Cell viability of the chemosensizers in breast cancer cells.....47
Figure 14: Cell viability of combinational treatment in the molar ratio of 1:5 and 1:10 in breast cancer cells.....48
Figure 15: Cell viability of combinational treatment in the molar ratio of 1:5 and 1:10 in breast cancer cells.....49
Figure 16: Cell viability of combinational treatment in the molar ratio of 1:1, 1:2, and 1:3 in breast cancer cells.....50
Figure 17: Cell viability of combinational treatment in the molar ratio of 1:1, 1:2, and 1:3 in breast cancer cells.....52
Figure 18: CI value of combinational treatment in the molar ratio of 1:5 and 1:10 in breast cancer cells.....54
Figure 19: CI value of combinational treatment in the molar ratio of 1:1, 1:2, and 1:3 in breast cancer cells.....55
Figure 20: The CI value comparision of different anticancer drugs combined with T1 in the molar ratio of 1:3 in breast cancer cells.....55
Figure 21: Western blotting analysis of efflux pump expressions after T1 treatment in breast cancer cells.....57
Figure 22: Western blotting analysis of efflux pump expressions after DTX and combined treatment of DTX and T1 in breast cancer cells.....59
Figure 23: Fluorescence images of DOX localization in breast cancer cells by inverted fluorescence microscope.....61
Figure 24: Particle size and its distribution in liposomes.....62
Figure 25: The standard curve of free drugs detected by HPLC.....63
Figure 26: The mice were measured after the drug treatment in tumor-bearing nude mice.....64
Figure 27: The individual tumor volume for each experimental group after treatment.....65

Table 1: Alternative name, gene locus, and tissue distribution of ABC transporters.....7
Table 2: Exogenous cytotoxic substrates for ABC transporters.....8
Table 3: Buffer formulation in Western blotting.....26
Table 4: IC50 value of anticancer drugs in human breast cancer cell lines.....46
Table 5: IC50 of chemosensizers in human breast cancer cell.....47
Table 6: IC50 and CI value of the combined drugs.....56
Table 7: Characterization of different liposomal formulations.....62
Table 8: Drug loading and encapsulation efficiency in DTX/T1 liposomes.....63

1.Eloy JO, Petrilli R, Topan JF, Antonio HMR, Barcellos JPA, Chesca DL, Serafini LN, Tiezzi DG, Lee RJ, Marchetti JM. Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids Surf B Biointerfaces 2016;141: 74-82.
2.Yin T, Wang L, Yin L, Zhou J, Huo M. Co-delivery of hydrophobic paclitaxel and hydrophilic AURKA specific siRNA by redox-sensitive micelles for effective treatment of breast cancer. Biomaterials 2015;61: 10-25.
3.Hutchinson L. Breast cancer: challenges, controversies, breakthroughs. Nat Rev Clin Oncol 2010;7: 669-70.
4.Tang Y, Soroush F, Tong Z, Kiani MF, Wang B. Targeted multidrug delivery system to overcome chemoresistance in breast cancer. Int J Nanomedicine 2017;12: 671-81.
5.Rojas K, Stuckey A. Breast Cancer Epidemiology and Risk Factors. Clin Obstet Gynecol 2016;59: 651-72.
6.Xu JW, Li QQ, Tao LL, Cheng YY, Yu J, Chen Q, Liu XP, Xu ZD. Involvement of EGFR in the promotion of malignant properties in multidrug resistant breast cancer cells. Int J Oncol 2011;39: 1501-9.
7.Society AC. Chemotherapy for Breast cancer. https://www.cancer.org/cancer/breast-cancer/treatment/chemotherapy-for-breast-cancer.html.
8.Sibaud V, Leboeuf NR, Roche H, Belum VR, Gladieff L, Deslandres M, Montastruc M, Eche A, Vigarios E, Dalenc F, Lacouture ME. Dermatological adverse events with taxane chemotherapy. Eur J Dermatol 2016;26: 427-43.
9.Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23: 5542-51.
10.Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 1991;83: 288-91.
11.Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1995;332: 1004-14.
12.Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl) 2012;6: 159-71.
13.Cortazar P, Justice R, Johnson J, Sridhara R, Keegan P, Pazdur R. US Food and Drug Administration approval overview in metastatic breast cancer. J Clin Oncol 2012;30: 1705-11.
14.Administration UFaD. Taxol. http://www.accessdata. fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetail. 2012.
15.Administration UFaD. Taxotere. http://www.accessdata.fda. gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. 2012.
16.Vetrivel KS, Dharmalingam K. Isolation and characterization of stable mutants of Streptomyces peucetius defective in daunorubicin biosynthesis. J Genet 2001;80: 31-8.
17.Cortes-Funes H, Coronado C. Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 2007;7: 56-60.
18.Nicholls G, Clark BJ, Brown JE. Solid-phase extraction and optimized separation of doxorubicin, epirubicin and their metabolites using reversed-phase high-performance liquid chromatography. J Pharm Biomed Anal 1992;10: 949-57.
19.Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 1976;36: 2891-5.
20.Zunina F, Gambetta R, Di Marco A. The inhibition in vitro of DNA polymerase and RNA polymerases by daunomycin and adriamycin. Biochem Pharmacol 1975;24: 309-11.
21.Wassermann K, Markovits J, Jaxel C, Capranico G, Kohn KW, Pommier Y. Effects of morpholinyl doxorubicins, doxorubicin, and actinomycin D on mammalian DNA topoisomerases I and II. Mol Pharmacol 1990;38: 38-45.
22.Guano F, Pourquier P, Tinelli S, Binaschi M, Bigioni M, Animati F, Manzini S, Zunino F, Kohlhagen G, Pommier Y, Capranico G. Topoisomerase poisoning activity of novel disaccharide anthracyclines. Mol Pharmacol 1999;56: 77-84.
23.Perez EA. Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Res Treat 2009;114: 195-201.
24.Wu Q, Yang Z, Nie Y, Shi Y, Fan D. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett 2014;347: 159-66.
25.Coley HM. Mechanisms and consequences of chemotherapy resistance in breast cancer. Ejc Supplements 2009;7: 3-7.
26.Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001;42: 1007-17.
27.Efferth T. The human ATP-binding cassette transporter genes: from the bench to the bedside. Curr Mol Med 2001;1: 45-65.
28.Sharom FJ, Liu R, Qu Q, Romsicki Y. Exploring the structure and function of the P-glycoprotein multidrug transporter using fluorescence spectroscopic tools. Semin Cell Dev Biol 2001;12: 257-65.
29.Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell International 2005;5.
30.Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992;258: 1650-4.
31.Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 1998;95: 15665-70.
32.Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999;59: 4559-63.
33.Kuo MT. Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 2007;608: 23-30.
34.Bell DR, Trent JM, Willard HF, Riordan JR, Ling V. Chromosomal location of human P-glycoprotein gene sequences. Cancer Genet Cytogenet 1987;25: 141-8.
35.Knutsen T, Rao VK, Ried T, Mickley L, Schneider E, Miyake K, Ghadimi BM, Padilla-Nash H, Pack S, Greenberger L, Cowan K, Dean M, Fojo T, Bates S. Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines. Genes Chromosomes Cancer 2000;27: 110-6.
36.Lal S, Mahajan A, Chen WN, Chowbay B. Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab 2010;11: 115-28.
37.Murray S, Briasoulis E, Linardou H, Bafaloukos D, Papadimitriou C. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies. Cancer Treat Rev 2012;38: 890-903.
38.Zelnak A. Overcoming taxane and anthracycline resistance. Breast J 2010;16: 309-12.
39.McGrogan BT, Gilmartin B, Carney DN, McCann A. Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta 2008;1785: 96-132.
40.Glavinas H, Mehn D, Jani M, Oosterhuis B, Heredi-Szabo K, Krajcsi P. Utilization of membrane vesicle preparations to study drug-ABC transporter interactions. Expert Opin Drug Metab Toxicol 2008;4: 721-32.
41.Al-Abd AM, Mahmoud AM, El-Sherbiny GA, El-Moselhy MA, Nofal SM, El-Latif HA, El-Eraky WI, El-Shemy HA. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro. Cell Prolif 2011;44: 591-601.
42.Riordan JR, Ling V. Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J Biol Chem 1979;254: 12701-5.
43.Rosenberg MF, Kamis AB, Callaghan R, Higgins CF, Ford RC. Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrate major conformational changes in the transmembrane domains upon nucleotide binding. Journal of Biological Chemistry 2003;278: 8294-9.
44.Senior AE, Bhagat S. P-glycoprotein shows strong catalytic cooperativity between the two nucleotide sites. Biochemistry 1998;37: 831-6.
45.Ni Z, Bikadi Z, Rosenberg MF, Mao Q. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 2010;11: 603-17.
46.Nivelle L, Hubert J, Courot E, Jeandet P, Aziz A, Nuzillard JM, Renault JH, Clement C, Martiny L, Delmas D, Tarpin M. Anti-Cancer Activity of Resveratrol and Derivatives Produced by Grapevine Cell Suspensions in a 14 L Stirred Bioreactor. Molecules 2017;22.
47.Venkatadri R, Muni T, Iyer AK, Yakisich JS, Azad N. Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death. Cell Death Dis 2016;7: e2104.
48.Aluyen JK, Ton QN, Tran T, Yang AE, Gottlieb HB, Bellanger RA. Resveratrol: potential as anticancer agent. J Diet Suppl 2012;9: 45-56.
49.Liu Y, Chen X, Li J. Resveratrol protects against oxidized lowdensity lipoproteininduced human umbilical vein endothelial cell apoptosis via inhibition of mitochondrialderived oxidative stress. Mol Med Rep 2017;15: 2457-64.
50.Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT. Resveratrol Suppresses Oxidative Stress and Inflammatory Response in Diethylnitrosamine-Initiated Rat Hepatocarcinogenesis. Cancer Prevention Research 2010;3: 753-63.
51.Gulcin I. Antioxidant properties of resveratrol: A structure-activity insight. Innovative Food Science & Emerging Technologies 2010;11: 210-8.
52.Xu J, Liu D, Niu H, Zhu G, Xu Y, Ye D, Li J, Zhang Q. Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. J Exp Clin Cancer Res 2017;36: 19.
53.Novelle MG, Wahl D, Dieguez C, Bernier M, de Cabo R. Resveratrol supplementation: Where are we now and where should we go? Ageing Res Rev 2015;21: 1-15.
54.Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 2005;16: 449-66.
55.Park EJ, Pezzuto JM. The pharmacology of resveratrol in animals and humans. Biochim Biophys Acta 2015;1852: 1071-113.
56.Lin CL, Hsieh SL, Leung W, Jeng JH, Huang GC, Lee CT, Wu CC. 2,3,5,4''-tetrahydroxystilbene-2-O-beta-D-glucoside suppresses human colorectal cancer cell metastasis through inhibiting NF-kappaB activation. Int J Oncol 2016;49: 629-38.
57.Lv G, Lou Z, Chen S, Gu H, Shan L. Pharmacokinetics and tissue distribution of 2,3,5,4''-tetrahydroxystilbene-2-O-beta-D-glucoside from traditional Chinese medicine Polygonum multiflorum following oral administration to rats. J Ethnopharmacol 2011;137: 449-56.
58.Ling S, Xu JW. Biological Activities of 2,3,5,4''-Tetrahydroxystilbene-2-O-beta-D-Glucoside in Antiaging and Antiaging-Related Disease Treatments. Oxid Med Cell Longev 2016;2016: 4973239.
59.Grech JN, Li Q, Roufogalis BD, Duck CC. Novel Ca(2+)-ATPase inhibitors from the dried root tubers of Polygonum Multiflorum. J Nat Prod 1994;57: 1682-7.
60.Tamura M, Koshibe Y, Kaji K, Ueda JY, Shirataki Y. Attempt to synthesize 2,3,5,4''-tetrahydroxystilbene derived from 2,3,5,4''-tetrahydroxystilbene-2-O-beta-glucoside (THSG). Chem Pharm Bull (Tokyo) 2015;63: 122-5.
61.Chang MJ, Xiao JH, Wang Y, Yan YL, Yang J, Wang JL. 2, 3, 5, 4''-Tetrahydroxystilbene-2-O-beta-D-glucoside improves gastrointestinal motility disorders in STZ-induced diabetic mice. PLoS One 2012;7: e50291.
62.Ryu SY, Han YN, Han BH. Monoamine oxidase-A inhibitors from medicinal plants. Archives of Pharmacal Research 1988;11: 230-9.
63.Kimura Y, Okuda H. Effects of naturally occurring stilbene glucosides from medicinal plants and wine, on tumour growth and lung metastasis in Lewis lung carcinoma-bearing mice. J Pharm Pharmacol 2000;52: 1287-95.
64.Lian T, Ho RJ. Trends and developments in liposome drug delivery systems. J Pharm Sci 2001;90: 667-80.
65.Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005;4: 145-60.
66.Muthu MS, Singh S. Targeted nanomedicines: effective treatment modalities for cancer, AIDS and brain disorders. Nanomedicine (Lond) 2009;4: 105-18.
67.Zhang H, Li RY, Lu X, Mou ZZ, Lin GM. Docetaxel-loaded liposomes: preparation, pH sensitivity, pharmacokinetics, and tissue distribution. J Zhejiang Univ Sci B 2012;13: 981-9.
68.Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965;13: 238-52.
69.Sessa G, Weissmann G. Phospholipid spherules (liposomes) as a model for biological membranes. J Lipid Res 1968;9: 310-8.
70.Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 1990;268: 235-7.
71.Torchilin VP, Klibanov AL, Huang L, O''Donnell S, Nossiff ND, Khaw BA. Targeted accumulation of polyethylene glycol-coated immunoliposomes in infarcted rabbit myocardium. FASEB J 1992;6: 2716-9.
72.Torchilin VP, Levchenko TS, Lukyanov AN, Khaw BA, Klibanov AL, Rammohan R, Samokhin GP, Whiteman KR. p-Nitrophenylcarbonyl-PEG-PE-liposomes: fast and simple attachment of specific ligands, including monoclonal antibodies, to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim Biophys Acta 2001;1511: 397-411.
73.Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22: 27-55.
74.Chou TC. Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Research 2010;70: 440-6.
75.Vinod BS, Nair HH, Vijayakurup V, Shabna A, Shah S, Krishna A, Pillai KS, Thankachan S, Anto RJ. Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2-Akt axis. Cell Death Discov 2015;1: 15061.
76.Schroeter A, Marko D. Resveratrol modulates the topoisomerase inhibitory potential of doxorubicin in human colon carcinoma cells. Molecules 2014;19: 20054-72.
77.Guo X, Zhao Z, Chen D, Qiao M, Wan F, Cun D, Sun Y, Yang M. Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors. Asian Journal of Pharmaceutical Sciences 2018.
78.Chen T, Wang C, Liu Q, Meng Q, Sun H, Huo X, Sun P, Peng J, Liu Z, Yang X, Liu K. Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway. Cancer Biol Ther 2015;16: 106-14.
79.Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2: 48-58.
80.Ren G, Liu D, Guo W, Wang M, Wu C, Guo M, Ai X, Wang Y, He Z. Docetaxel prodrug liposomes for tumor therapy: characterization, in vitro and in vivo evaluation. Drug Deliv 2016;23: 1272-81.
81.Shigehiro T, Masuda J, Saito S, Khayrani AC, Jinno K, Seno A, Vaidyanath A, Mizutani A, Kasai T, Murakami H, Satoh A, Ito T, Hamada H, Seno Y, Mandai T, Seno M. Practical Liposomal Formulation for Taxanes with Polyethoxylated Castor Oil and Ethanol with Complete Encapsulation Efficiency and High Loading Efficiency. Nanomaterials (Basel) 2017;7.