Integration of phytochemicals and phytotherapy into cancer precision medicine

Oncotarget

Volumn 8, Issue 30, 2017, Pages 50284-50304

  Efferth, Thomas ^a   Saeed, Mohamed E M ^a   Mirghani, Elhaj ^b   Alim, Awadh ^b   Yassin, Zahir ^d   Saeed, Elfatih ^e   Khalid, Hassan E ^f   Daak, Salah ^b,c  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

^b Dr Salah Wanesi Foundation for Cancer Research and Control   (Sudan)

^c UNIVERSITY OF KHARTOUM   (Sudan)

^d Tayba Cancer Centre   (Sudan)

^e Sudan National Government   (Sudan)

^f UNIVERSITY OF KHARTOUM   (Sudan)

Author keywords

Drug resistance; Network pharmacology; Polypharmacology; Targeted chemotherapy

Indexed keywords

CAMPTOTHECIN; CHRYSIN; CRYPTOTANSHINONE; CUCURBITACIN; DNA; EPIGALLOCATECHIN GALLATE; ETOPOSIDE; GEFITINIB; GLUCOSE PENTAGALLATE; MATRINE; PACLITAXEL; PLANT MEDICINAL PRODUCT; PODOPHYLLOTOXIN; QUERCETIN; RESVERATROL; RNA; STAT3 PROTEIN; TENIPOSIDE; VEMURAFENIB; VINCA ALKALOID; WITHAFERIN A; PHYTOCHEMICAL;

ARTICLE; BIOINFORMATICS; CANCER GROWTH; CELL SUBPOPULATION; CYTOTOXICITY; DIAGNOSTIC TEST; DNA BINDING; DNA SEQUENCE; GENOMIC INSTABILITY; HUMAN; IN VITRO STUDY; MALIGNANT NEOPLASM; ONCOLOGY; PERSONALIZED MEDICINE; PHARMACOGENOMICS; PHYTOTHERAPY; POINT MUTATION; PROSPECTIVE STUDY; RNA SEQUENCE; SINGLE NUCLEOTIDE POLYMORPHISM; TRADITIONAL MEDICINE; TREATMENT FAILURE; TREATMENT RESPONSE; TUMOR CELL; METABOLISM; PROCEDURES;

HUMANS; PHYTOCHEMICALS; PHYTOTHERAPY; PRECISION MEDICINE;

EID: 85025812126     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.17466     Document Type: Article

References (145)

1. Rhoads CP. Report on a cooperative study of nitrogen mustard (HN2) therapy of neoplastic disease. Transactions the the asociation of American physicians. 1947; 60:110-117.
2. Pinedo HM, Giaccone G. (1998). Drug Resistance in the Treatment of Cancer. (Cambridge: Cambridge University Press).
3. Volm M, Mattern J. Resistance mechanisms and their regulation in lung cancer. Critical reviews in oncogenesis. 1996; 7:227-244.
4. Mellor HR, Callaghan R. Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology. 2008; 81:275-300.
5. Mattern J, Volm M. Clinical relevance of predictive tests for cancer chemotherapy. Cancer treatment reviews. 1982; 9:267-298.
6. Lippert TH, RuoffHJ, Volm M. Could a revision of the current guidelines for cancer drug use improve the quality of cancer treatment? Therapeutics and clinical risk management. 2014; 10:69-72.
7. Schmitt MW, Loeb LA, Salk JJ. The influence of subclonal resistance mutations on targeted cancer therapy. Nature reviews Clinical oncology. 2016; 13:335-347.
8. Walther Z, Sklar J. Molecular tumor profiling for prediction of response to anticancer therapies. Cancer journal. 2011; 17:71-79.
9. Efferth T, Konkimalla VB, Wang YF, Sauerbrey A, Meinhardt S, Zintl F, Mattern J, Volm M. Prediction of broad spectrum resistance of tumors towards anticancer drugs. Clinical cancer research. 2008; 14:2405-2412.
10. Volm M, Efferth T. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine. Frontiers in oncology. 2015; 5:282.
11. Blumenthal RD, Goldenberg DM. Methods and goals for the use of in vitro and in vivo chemosensitivity testing. Molecular biotechnology. 2007; 35:185-197.
12. Wu JZ. [Tetrazolium-based colorimetric assay (MTT) and its application in chemosensitivity testing of antitumor Chinese medicine] (Article in Chinese). Zhonghua Kou Qiang Yi Xue Za Zhi. 1992; 27:373-375.
13. Efferth T, Volm M. Pharmacogenetics for individualized cancer chemotherapy. Pharmacology and therapeutics. 2005; 107:155-176.
14. Dopazo J. Genomics and transcriptomics in drug discovery. Drug discovery today. 2014; 19:126-132.
15. Feero WG, Guttmacher AE, Collins FS. Genomic medicine-an updated primer. The new England journal of medicine. 2010; 362:2001-2011.
16. Jiang L, Huang L, Kuang Q, Zhang J, Li M, Wen Z, He L. Improving the prediction of chemotherapeutic sensitivity of tumors in breast cancer via optimizing the selection of candidate genes. Computational biology and chemistry. 2014; 49:71-78.
17. Yue Z, Zhang W, Lu Y, Yang Q, Ding Q, Xia J, Chen Y. Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties. Peer journal. 2015; 3:e1425.
18. Sun Y, Zhang W, Chen Y, Ma Q, Wei J, Liu Q. Identifying anti-cancer drug response related genes using an integrative analysis of transcriptomic and genomic variations with cell line-based drug perturbations. Oncotarget. 2016; 7:9404-19. doi: 10.18632/oncotarget.7012.
19. Chan SL, Wong AM, Lee K, Wong N, Chan AK. Personalized therapy for hepatocellular carcinoma: Where are we now? Cancer treatment reviews. 2016; 45:77-86.
20. Chang W, Brohl AS, Patidar R, Sindiri S, Shern JF, Wei JS, Song YK, Yohe ME, Gryder BE, Zhang S, al e. Multidimensional ClinOmics for precision therapy of children and adolescent young adults with relapsed and refractory cancer: A report from the Center for Cancer Research. Clinical cancer research. 2016.
21. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The new England journal of medicine. 2012; 366:883-892.
22. Creixell P, Schoof EM, Erler JT, Linding R. Navigating cancer network attractors for tumor-specific therapy. Nature biotechnology. 2012; 30:842-848.
23. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313:1929-1935.
24. Mullard A. 2011 FDA drug approvals. Nature reviews in drug discovery. 2012; 11:91-94.
25. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nature reviews in drug discovery. 2004; 3:711-715.
26. Aronson JK. Old drugs-new uses. British journal of clinical pharmacology. 2007; 64:563-565.
27. Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nature reviews in drug discovery. 2004; 3:673-683.
28. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth defects research part C, embryo today: reviews. 2015; 105:140-156.
29. Walker SL, Waters MF, Lockwood DN. The role of thalidomide in the management of erythema nodosum leprosum. Leprosy reviews. 2007; 78:197-215.
30. Moehler T. Clinical experience with thalidomide and lenalidomide in multiple myeloma. Current cancer drug targets. 2012; 12:372-390.
31. Sirota M, Dudley JT, Kim J, Chiang AP, Morgan AA, Sweet-Cordero A, Sage J, Butte AJ. Discovery and preclinical validation of drug indications using compendia of public gene expression data. Science translational medicine. 2011; 3:96ra77.
32. Schmidt F, Efferth T. Tumor Heterogeneity, Single-Cell Sequencing, and Drug Resistance. Pharmaceuticals (Basel). 2016; 9(2).
33. Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. Journal of natural products. 2007; 70:461-477.
34. Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Current drug targets. 2006; 7:407-421.
35. Kuete V, Efferth T. Cameroonian medicinal plants: Pharmacology and derived natural product. Frontiers in pharmacology. 2010; 1:123.
36. Kuete V, Efferth T. Pharmacogenomics of Cameroonian traditional herbal medicine for cancer therapy. Journal of ethnopharmacology. 2011; 137:752-766.
37. Wink M. Plant breeding: importance of plant secondary metabolites for protection against pathogens and herbivores. Theoretical and applied genetics. 1988; 75:225-233.
38. Wöll S, Kim SH, Efferth T. Animal plant warfare and secondary metabolite evolution. Natural products and bioprospecting. 2013; 3:1-7.
39. Efferth T, Miyachi H, Drexler HG, Gebhart E. Methylthioadenosine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells. Blood cells, molecules and diseases. 2002; 28:47-56.
40. Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer research. 2008; 68:4347-4351.
41. Efferth T, Zacchino S, Georgiev MI, Liu L, Wagner H, Panossian A. Nobel Prize for artemisinin brings phytotherapy into the spotlight. Phytomedicine. 2015; 22:A1-3.
42. Efferth T, Greten HJ. Quality Control for Medicinal Plants. Medicinal and Aromatic plants (Los Angeles). 2012;1:7.
43. Efferth T, Greten HJ. The European directive on traditional herbal medicinal products: friend or foe for plant-based therapies? Zhong Xi Yi Jie He Xue Bao. 2012; 10:357-361.
44. Efferth T, Banerjee M, Paul NW, Abdelfatah S, Arend J, Elhassan G, Hamdoun S, Hamm R, Hong C, Kadioglu O, Nass J, Ochwangi D, Ooko E, et al. Biopiracy of natural products and good bioprospecting practice. Phytomedicine. 2016; 23:166-173.
45. Efferth T, Fu YJ, Zu YG, Schwarz G, Konkimalla VS, Wink M. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Current medicinal chemistry. 2007; 14:2024-2032.
46. Efferth T. Personalized Cancer Medicine: From molecular diagnostics to targeted therapy with natural products. Planta medica. 2010; 76:1-12.
47. Efferth T. Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules. Current medicinal chemistry. 2012; 19:5735-5744.
48. Wahl O, Oswald M, Tretzel L, Herres E, Arend J, Efferth T. Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products. Current medicinal chemistry. 2011; 18:3136-3155.
49. Saeed ME, Abdelgadir H, Sugimoto Y, Khalid HE, Efferth T. Cytotoxicity of 35 medicinal plants from Sudan towards sensitive and multidrug-resistant cancer cells. Journal of ethnopharmacology. 2015; 174:644-58.
50. Saeed ME, Meyer M, Hussein A, Efferth T. Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells. Journal of ethnopharmacology. 2016; 186:209-23.
51. Omosa LK, Midiwo JO, Masila VM, Gisacho BM, Munayi R, Francisca-Kamakama, Chemutai KP, Elhaboob G, Saeed ME, Hamdoun S, Kuete V, Efferth T. Cytotoxicity of 91 Kenyan indigenous medicinal plants towards human CCRFCEM leukemia cells. Journal of ethnopharmacology. 2016; 179:177-96.
52. Gillet JP, Efferth T, Remacle J. Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochimica et biophysica Acta 2007; 1775:237-262.
53. Saeed M, Khalid H, Sugimoto Y, Efferth T. The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: pharmacogenomic determination of genes associated with sensitivity or resistance. Phytomedicine. 2014; 21:689-96.
54. Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu SH, Cheng YC. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Science translational medicine. 2010; 2:45ra59.
55. K. Schröder S, Beckmann K, Franconi G, Meyer-Hamme G, Friedemann T, Greten HJ, Rostock M, Efferth T. Can medical herbs stimulate regeneration or neuroprotection and treat neuropathic pain in chemotherapy-induced peripheral neuropathy? Evidence-based complementary and alternative medicine. 2013; 2013:423713.
56. Meyer-Hamme G, Beckmann K, Radtke J, Efferth T, Greten HJ, Rostock M, Schröder S. A Survey of Chinese Medicinal Herbal Treatment for Chemotherapy-Induced Oral Mucositis. Evidence-based complementary and alternative medicine. 2013; 2013:284959.
57. Fong SY, Efferth TH, Zuo Z. Modulation of the pharmacokinetics, therapeutic and adverse effects of NSAIDs by Chinese herbal medicines. Expert opinion on drug metabolism and toxicology. 2014; 10:1711-39.
58. Kim DJ, Chan KS, Sano S, Digiovanni J. Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis. Molecular carcinogenesis. 2007; 46:725-31.
59. Resemann HK, Watson CJ, Lloyd-Lewis B. The Stat3 paradox: a killer and an oncogene. Molecular and cellular endocrinology. 2014; 382:603-11.
60. Zhang HF, Lai R. STAT3 in Cancer-Friend or Foe? Cancers (Basel). 2014; 6:1408-40.
61. Furtek SL, Backos DS, Matheson CJ, Reigan P. Strategies and Approaches of Targeting STAT3 for Cancer Treatment. ACS chemical biology. 2016; 11:308-18.
62. Park IH, Li C. Characterization of molecular recognition of STAT3 SH2 domain inhibitors through molecular simulation. Journal of molecular recognition. 2011; 24:254-265.
63. Efferth T, Koch E. Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy. Current drug targets. 2011; 12:122-132.
64. Saeed M, Jacob S, Sandjo LP, Sugimoto Y, Khalid HE, Opatz T, Thines E, Efferth T. Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells. Frontiers in pharmacology. 2015; 6:267.
65. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nature chemical biology. 2008; 4:682-690.
66. Xie L, Xie L, Kinnings SL, Bourne PE. Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Annual review of pharmacology and toxicology. 2012; 52:361-379.
67. Azmi AS, Mohammad RM. Rectifying cancer drug discovery through network pharmacology. Future medicinal chemistry. 2014; 6:529-539.
68. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nature reviews genetics. 2011; 12:56-68.
69. Espinoza-Fonseca LM. The benefits of the multi-target approach in drug design and discovery. Bioorganic and medicinal chemistry. 2006; 14:896-897.
70. Mencher SK, Wang LG. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC clinical pharmacology. 2005; 5:3.
71. Chandra N, Padiadpu J. Network approaches to drug discovery. Expert opinion on drug discovery. 2013; 8(1):7-20.
72. Azmi AS, Wang Z, Philip PA, Mohammad RM, Sarkar FH. Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Molecular cancer therapeutics. 2010; 9:3137-3144.
73. Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL. The human disease network. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104:8685-8690.
74. Kibble M, Saarinen N, Tang J, Wennerberg K, Makela S, Aittokallio T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Natural product reports. 2015; 32:1249-1266.
75. Zhang GB, Li QY, Chen QL, Su SB. Network pharmacology: a new approach for Chinese herbal medicine research. Evidence-based complementary and alternative medicine. 2013; 2013:621423.
76. Pache RA, Ceol A, Aloy P. NetAligner-a network alignment server to compare complexes, pathways and whole interactomes. Nucleic acids research. 2012; 40(Web Server issue):W157-161.
77. Anighoro A, Bajorath J, Rastelli G. Polypharmacology: challenges and opportunities in drug discovery. Journal of medicinal chemistry. 2014; 57:7874-7887.
78. Rask-Andersen M, Zhang J, Fabbro D, Schioth HB. Advances in kinase targeting: current clinical use and clinical trials. Trends in pharmacological sciences. 2014; 35:604-620.
79. Azmi AS. Network pharmacology for cancer drug discovery: are we there yet? Future medicinal chemistry. 2012; 4:939-941.
80. Cerami E, Demir E, Schultz N, Taylor BS, Sander C. Automated network analysis identifies core pathways in glioblastoma. PLoS one. 2010; 5:e8918.
81. Jaeger S, Min J, Nigsch F, Camargo M, Hutz J, Cornett A, Cleaver S, Buckler A, Jenkins JL. Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer. Journal of biomolecular screening. 2014; 19:791-802.
82. Neapolitan R, Jiang X. Inferring Aberrant Signal Transduction Pathways in Ovarian Cancer from TCGA Data. Cancer informatics. 2014; 13:29-36.
83. Leiserson MD, Vandin F, Wu HT, Dobson JR, Eldridge JV, Thomas JL, Papoutsaki A, Kim Y, Niu B, McLellan M, Lawrence MS, Gonzalez-Perez A, Tamborero D, et al. Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. Nature genetics. 2015; 47:106-114.
84. Gevaert O, Villalobos V, Sikic BI, Plevritis SK. Identification of ovarian cancer driver genes by using module network integration of multi-omics data. Interface focus. 2013; 3:20130013.
85. Xu X. New concepts and approaches for drug discovery based on traditional Chinese medicine. Drug discovery today. Technologies. 2006; 3:247-253.
86. Cheung F. TCM: Made in China. Nature. 2011; 480:S82-83.
87. Azmi AS. Adopting network pharmacology for cancer drug discovery. Current drug discovery technologies. 2013; 10:95-105.
88. Li S, Fan TP, Jia W, Lu A, Zhang W. Network pharmacology in traditional Chinese medicine. Evidencebased complementary and alternative medicine. 2014; 2014:138460.
89. Engin HB, Gursoy A, Nussinov R, Keskin O. Networkbased strategies can help mono-and poly-pharmacology drug discovery: a systems biology view. Current pharmaceutical design. 2014; 20(8):1201-1207.
90. Korcsmaros T, Szalay MS, Bode C, Kovacs IA, Csermely P. How to design multi-target drugs. Expert opinion on drug discovery. 2007; 2:799-808.
91. Jeong H, Mason SP, Barabasi AL, Oltvai ZN. Lethality and centrality in protein networks. Nature. 2001; 411:41-42.
92. Hao da C, Xiao PG. Network pharmacology: a Rosetta Stone for traditional Chinese medicine. Drug development research. 2014; 75:299-312.
93. Morphy R, Kay C, Rankovic Z. From magic bullets to designed multiple ligands. Drug discovery today. 2004; 9:641-651.
94. Hopkins AL, Mason JS, Overington JP. Can we rationally design promiscuous drugs? Current opinion in structural biology. 2006; 16:127-136.
95. Jackson RA, Chen ES. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs. Pharmacology and therapeutics. 2016; 162:69-85.
96. Wang Z, Li J, Dang R, Liang L, Lin J. PhIN: A Protein Pharmacology Interaction Network Database. CPT Pharmacometrics and system pharmacology. 2015; 4:e00025.
97. Kitano H. Towards a theory of biological robustness. Molecular systems biology. 2007; 3:137.
98. Zhang S, Shan L, Li Q, Wang X, Li S, Zhang Y, Fu J, Liu X, Li H, Zhang W. Systematic Analysis of the Multiple Bioactivities of Green Tea through a Network Pharmacology Approach. Evidence-based complementary and alternative medicine. 2014; 2014:512081.
99. Luo F, Gu J, Chen L, Xu X. Systems pharmacology strategies for anticancer drug discovery based on natural products. Molecular biosystems. 2014; 10:1912-1917.
100. Liu J, Pei M, Zheng C, Li Y, Wang Y, Lu A, Yang L. A systems-pharmacology analysis of herbal medicines used in health improvement treatment: predicting potential new drugs and targets. Evidence-based complementary and alternative medicine. 2013; 2013:938764.
101. Suarez-Kurtz G, Vargens DD, Santoro AB, Hutz MH, de Moraes ME, Pena SD, Ribeiro-dos-Santos A, Romano-Silva MA, Struchiner CJ. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population. PLoS one. 2014; 9:e83472.
102. Radovich M, Clare SE, Atale R, Pardo I, Hancock BA, Solzak JP, Kassem N, Mathieson T, Storniolo AM, Rufenbarger C, Lillemoe HA, Blosser RJ, Choi MR, et al. Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing. Breast cancer research and treatment. 2014; 143:57-68.
103. Efferth T. Stem cells, cancer stem-like cells, and natural products. Planta medica 2012; 78:935-942.
104. Pistollato F, Giampieri F, Battino M. The use of plantderived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. Food and chemical toxicology 2015; 75:58-70.
105. Seo EJ, Wiench B, Hamm R, Paulsen M, Zu Y, Fu Y, Efferth T. Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres. Phytomedicine 2015; 22:438-443.
106. Bassa LM, Jacobs C, Gregory K, Henchey E, Ser-Dolansky J, Schneider SS. Rhodiola crenulata induces an early estrogenic response and reduces proliferation and tumorsphere formation over time in MCF7 breast cancer cells. Phytomedicine 2016; 23: 87-94.
107. Naveen CR, Gaikwad S, Agrawal-Rajput R. Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells. Phytomedicine 2016; 23: 736-744.
108. Atherly AJ, Camidge DR. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. British journal of cancer. 2012; 106:1100-6
109. Antoñanzas F, Juárez-Castelló CA, Rodríguez-Ibeas R. Some economics on personalized and predictive medicine. The European journal of health economics. 2015; 16:985-994.
110. Doble B, Tan M, Harris A, Lorgelly P. Modeling companion diagnostics in economic evaluations of targeted oncology therapies: systematic review and methodological checklist. Expert review of molecular diagnostics. 2015; 15:235-54.
111. Morgan G, Aftimos P, Awada A. Current-day precision oncology: from cancer prevention, screening, drug development, and treatment-have we fallen short of the promise? Current opinion in oncology. 2016; 28:441-6.
112. Kresty LA, Mallery SR, Stoner GD. Black raspberries in cancer clinical trials: Past, present and future. Journal of berry research 2016; 6:251-261.
113. Weh KM, Aiyer HS, Howell AB, Kresty LA. Cranberry proanthocyanidins modulate reactive oxygen species in Barrett's and esophageal adenocarcinoma cell lines. Journal of Berry research 2016; 6:125-136.
114. Derosa G, Romano D, D'Angelo A, Maffioli P. Berberis aristata/Silybum marianum fixed combination (Berberol(®)) effects on lipid profile in dyslipidemic patients intolerant to statins at high dosages: a randomized, placebo-controlled, clinical trial. Phytomedicine 2015; 22:231-237.
115. Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebocontrolled clinical trial. Phytomedicine 2015;22: 290-296.
116. Mao JJ, Xie SX, Zee J, Soeller I, Li QS, Rockwell K, Amsterdam JD. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine 2015; 22:394-399.
117. Lin Y, Kazlova V, Ramakrishnan S, Murray MA, Fast D, Chandra A, Gellenbeck KW. Bone health nutraceuticals alter microarray mRNA gene expression: A randomized, parallel, open-label clinical study. Phytomedicine 2016; 23: 18-26.
118. Maulik SK, Wilson V, Seth S, Bhargava B, Dua P, Ramakrishnan S, Katiyar CK. Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb. ex DC.) Wight & Arn. in patients of chronic heart failure: a doubleblind, randomized controlled trial. Phytomedicine 2016; 23: 1211-1219.
119. Mao JJ, Xie SX, Keefe JR, Soeller I, Li QS, Amsterdam JD. Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial. Phytomedicine 2016; 23: 1735-1742.
120. Bharti AC, Donato N, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. Journal of immunology. 2003; 171:3863-3871.
121. Chakravarti N, Myers JN, Aggarwal BB. Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). International journal of cancer. 2006; 119:1268-1275.
122. Shin DS, Kim HN, Shin KD, Yoon YJ, Kim SJ, Han DC, Kwon BM. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer research. 2009; 69:193-202.
123. Ge Y, Yang B, Xu X, Dai Q, Chen Z, Cheng R. Cryptotanshinone acts synergistically with imatinib to induce apoptosis of human chronic myeloid leukemia cells. Leukemia and lymphoma. 2015; 56:730-738.
124. Masuda M, Suzui M, Weinstein IB. Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clinical cancer research. 2001; 7:4220-4229.
125. Tang SN, Fu J, Shankar S, Srivastava RK. EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS one. 2012; 7:e31067.
126. Senggunprai L, Kukongviriyapan V, Prawan A, Kukongviriyapan U. Quercetin, EGCG exhibit chemopreventive effects in cholangiocarcinoma cells via suppression of JAK/STAT signaling pathway. Phytotherapy research. 2014; 28:841-848.
127. Rajendran P, Li F, Shanmugam MK, Vali S, Abbasi T, Kapoor S, Ahn KS, Kumar AP, Sethi G. Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1. Journal of cellular physiology. 2012; 227:2184-2195.
128. Saeed M, Kuete V, Kadioglu O, Bortzler J, Khalid H, Greten HJ, Efferth T. Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drugresistant tumor cells as determined by pharmacogenomics and molecular docking. Phytomedicine. 2014; 21:1525-1533.
129. Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007; 109:2293-2302.
130. Yu LJ, Wu ML, Li H, Chen XY, Wang Q, Sun Y, Kong QY, Liu J. Inhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells. Neoplasia. 2008; 10:736-744.
131. Yang T, Liu J, Yang M, Huang N, Zhong Y, Zeng T, Wei R, Wu Z, Xiao C, Cao X, Li M, Li L, Han B, Yu X, et al. Cucurbitacin B exerts anti-cancer activities in human multiple myeloma cells in vitro and in vivo by modulating multiple cellular pathways. Oncotarget. 2017;8:5800-5813. doi: 10.18632/oncotarget.10584.
132. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer research. 2003; 63:1270-1279.
133. Lee HJ, Seo NJ, Jeong SJ, Park Y, Jung DB, Koh W, Lee EO, Ahn KS, Lu J, Kim SH. Oral administration of penta-O-galloyl-beta-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition. Carcinogenesis. 2011; 32:804-811.
134. Zhang X, Blaskovich MA, Forinash KD, Sebti SM. Withacnistin inhibits recruitment of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumours. British journal of cancer. 2014; 111:894-902.
135. Bharadwaj U, Eckols TK, Kolosov M, Kasembeli MM, Adam A, Torres D, Zhang X, Dobrolecki LE, Wei W, Lewis MT, Dave B, Chang JC, Landis MD, et al. Drugrepositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Oncogene. 2015; 34:1341-1353.
136. Leeman-Neill RJ, Wheeler SE, Singh SV, Thomas SM, Seethala RR, Neill DB, Panahandeh MC, Hahm ER, Joyce SC, Sen M, Cai Q, Freilino ML, Li C, et al. Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3. Carcinogenesis. 2009; 30:1848-1856.
137. Yang N, Han F, Cui H, Huang J, Wang T, Zhou Y, Zhou J. Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling. Pharmacology reports. 2015; 67:388-393.
138. Yu X, He L, Cao P, Yu Q. Eriocalyxin B Inhibits STAT3 Signaling by Covalently Targeting STAT3 and Blocking Phosphorylation and Activation of STAT3. PLoS one. 2015; 10:e0128406.
139. Jeon YJ, Jung SN, Yun J, Lee CW, Choi J, Lee YJ, Han DC, Kwon BM. Ginkgetin inhibits the growth of DU-145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity. Cancer science. 2015; 106:413-420.
140. Liu J, Zhang Q, Ye Y, Li W, Qiu J, Zhan R, Chen W, Yu Q. Angoline: a selective IL-6/STAT3 signaling pathway inhibitor isolated from Zanthoxylum nitidum. Phytomedicine. 2014; 21:1088-1091.
141. Yco LP, Mocz G, Opoku-Ansah J, Bachmann AS. Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma. Biochemistry insights. 2014; 7:1-13.
142. Lirdprapamongkol K, Sakurai H, Abdelhamed S, Yokoyama S, Athikomkulchai S, Viriyaroj A, Awale S, Ruchirawat S, Svasti J, Saiki I. Chrysin overcomes TRAIL resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3 phosphorylation. International journal of oncology. 2013; 43:329-337.
143. Kang SH, Jeong SJ, Kim SH, Kim JH, Jung JH, Koh W, Kim DK, Chen CY. Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling. PLoS one. 2012; 7:e28706.
144. Funakoshi-Tago M, Tago K, Nishizawa C, Takahashi K, Mashino T, Iwata S, Inoue H, Sonoda Y, Kasahara T. Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation. Biochemical pharmacology. 2008; 76:1681-1693.
145. Zhang X, Yue P, Page BD, Li T, Zhao W, Namanja AT, Paladino D, Zhao J, Chen Y, Gunning PT, Turkson J. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109:9623-9628.