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Integration of Phytochemicals and Phytotherapy into Cancer Precision Medicine

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Approaching Complex Diseases

Part of the book series: Human Perspectives in Health Sciences and Technology ((HPHST,volume 2))

Abstract

The concept of personalized medicine initially formed in the 1970s and 1980s was substantially based on predictive in vitro tests for individual drug responsiveness of cancer patients, which did, however, not reach generally accepted clinical routine use. The standard drug regimens are limited by the development of drug resistance and severe side effects. Therefore, a priori predictive diagnostics, whether or not an individual patient would benefit from chemotherapy or suffer from its side effects would considerably improve treatment outcomes.

With the advent of novel genome-, transcriptome- and proteome-wide technologies as well as targeted therapy options, the idea of personalized medicine gained new interest again. Network pharmacology comprises a wide range of methods from bioinformatics, systems biology, molecular pharmacology, drug discovery, etc.

In addition to synthetic small molecules and more recently therapeutic antibodies, natural products always hold great importance to fight cancer. Vinca alkaloids, camptothecin derivatives, taxanes, epipodophyllotoxins, etc. are prominent examples for the success of phytochemicals and their derivatives in clinical oncology during the past decades. Therefore, plant-derived natural products may also offer a valuable resource for the development of targeted drugs in the era of “-omics” technologies and precision medicine. Network pharmacology represents a new emerging approach to understand the complex pharmacogenomic networks and new signaling organizations not only involved in tumor development but also in response of tumors to therapy.

In the present chapter, we give a conceptual overview that the activity of phytochemicals and medicinal plants is determined by genetic factors in a comparable manner as synthetic drugs too. This raises the possibility that natural products may be integrated into cancer chemotherapy protocols to overcome drug resistance towards established drugs. We feel that the use of scientific methods from evidence-based medicine (including network pharmacology and precision medicine) will facilitate the integration of natural products with proven bioactivity into conventional medicine to improve curing rates in clinical oncology.

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Abbreviations

ABC:

ATP-binding cassette

As2O3:

arsenic trioxide

CAR:

combination activity relationship

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

FAEW:

Free and Easy Wanderer

FEC:

5-fluorouracil, epirubicin and cyclophosphamide

FDA:

Food and Drug Administration

FGSTs:

first-generation sequencing technologies

HIV:

human immunodeficiency virus

HGF:

hepatocyte growth factor

JAK:

Janus kinase

MBSC:

Modeling based scientific computing

MDR:

multidrug resistance

NCI:

National Cancer Institute

NGSTs:

next-generation sequencing technologies

PI3K:

phosphoinositide 3 kinase

TCM:

Traditional Chinese Medicine

TCM-ID:

Traditional Chinese Medicine Information Database

TCMID:

Traditional Chinese Medicine Integrated Database

TCMLARS:

the traditional Chinese medical literature analysis and retrieval system

PharmDB-K:

The integrated bio-pharmacological Traditional Korean Medicine (TKM) database

SAR:

structure activity relationship

STAT3:

signal transducer and activator of transcription 3

SV40:

Simian vacuolating virus 40

T-ALL:

T cell acute lymphoblastic leukemia

TGSTs:

third-generation sequencing technologies

VEGF:

vascular endothelial growth factor

References

  1. Al-Lazikani, B., U. Banerji, and P. Workman. 2012. Combinatorial drug therapy for cancer in the post-genomic era. Natural Biotechnology 30: 679–692.

    Article  CAS  Google Scholar 

  2. Alves-Silva, J.M., A. Romane, T. Efferth, and L. Salgueiro. 2017. North African medicinal plants traditionally used in cancer therapy. Frontiers in Pharmacology 8: 383.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Amin, A., H. Gali-Muhtasib, M. Ocker, and R. Schneider-Stock. 2009a. Overview of major classes of plant-derived anticancer drugs. International Journal of Biomedical Sciences 5: 1–11.

    CAS  Google Scholar 

  4. Amin, A.R.M.R., O. Kucuk, F.R. Khuri, and D.M. Shin. 2009b. Perspectives for cancer prevention with natural compounds. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 27: 2712–2725.

    Article  CAS  Google Scholar 

  5. Anfosso, L., T. Efferth, A. Albini, and U. Pfeffer. 2006. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. The Pharmacogenomics Journal 6: 269.

    Article  CAS  PubMed  Google Scholar 

  6. Antoñanzas, F., C. Juárez-Castelló, and R. Rodríguez-Ibeas. 2015. Some economics on personalized and predictive medicine. The European Journal of Health Economics 16: 985–994.

    Article  PubMed  Google Scholar 

  7. Ashburn, T.T., and K.B. Thor. 2004. Drug repositioning: Identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery 3: 673–683.

    Article  CAS  PubMed  Google Scholar 

  8. Atherly, A.J., and D.R. Camidge. 2012. The cost-effectiveness of screening lung cancer patients for targeted drug sensitivity markers. British Journal of Cancer 106: 1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bagchi, D. 2014. Nutraceutical and functional food regulations in the United States and around the World. London: Academic Press.

    Google Scholar 

  10. Barnes, J., A.J. Mclachlan, C.M. Sherwin, and E.Y. Enioutina. 2016. Herbal medicines: challenges in the modern world. Part 1 Australia and New Zealand. Expert Review of Clinical Pharmacology 9: 905–915.

    Article  CAS  PubMed  Google Scholar 

  11. Begley, C.G., and L.M. Ellis. 2012. Raise standards for preclinical cancer research. Nature 483: 531.

    Article  CAS  PubMed  Google Scholar 

  12. Bentley, D.R., S. Balasubramanian, H.P. Swerdlow, G.P. Smith, J. Milton, C.G. Brown, K.P. Hall, D.J. Evers, C.L. Barnes, H.R. Bignell, J.M. Boutell, J. Bryant, R.J. Carter, R. Keira Cheetham, A.J. Cox, D.J. Ellis, M.R. Flatbush, N.A. Gormley, S.J. Humphray, L.J. Irving, M.S. Karbelashvili, S.M. Kirk, H. Li, X. Liu, K.S. Maisinger, L.J. Murray, B. Obradovic, T. Ost, M.L. Parkinson, M.R. Pratt, I.M. Rasolonjatovo, M.T. Reed, R. Rigatti, C. Rodighiero, M.T. Ross, A. Sabot, S.V. Sankar, A. Scally, G.P. Schroth, M.E. Smith, V.P. Smith, A. Spiridou, P.E. Torrance, S.S. Tzonev, E.H. Vermaas, K. Walter, X. Wu, L. Zhang, M.D. Alam, C. Anastasi, I.C. Aniebo, D.M. Bailey, I.R. Bancarz, S. Banerjee, S.G. Barbour, P.A. Baybayan, V.A. Benoit, K.F. Benson, C. Bevis, P.J. Black, A. Boodhun, J.S. Brennan, J.A. Bridgham, R.C. Brown, A.A. Brown, D.H. Buermann, A.A. Bundu, J.C. Burrows, N.P. Carter, N. Castillo, Chiara ECM, S. Chang, R. Neil Cooley, N.R. Crake, O.O. Dada, K.D. Diakoumakos, B. Dominguez-Fernandez, D.J. Earnshaw, U.C. Egbujor, D.W. Elmore, S.S. Etchin, M.R. Ewan, M. Fedurco, L.J. Fraser, K.V. Fuentes Fajardo, W. Scott Furey, D. George, K.J. Gietzen, C.P. Goddard, G.S. Golda, P.A. Granieri, D.E. Green, D.L. Gustafson, N.F. Hansen, K. Harnish, C.D. Haudenschild, N.I. Heyer, M.M. Hims, J.T. Ho, A.M. Horgan, et al. 2008. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456: 53–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Block, G., B. Patterson, and A. Subar. 1992. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutrition and Cancer 18: 1–29.

    Article  CAS  PubMed  Google Scholar 

  14. Bonifazi, P., M. Goldin, M.A. Picardo, I. Jorquera, A. Cattani, G. Bianconi, A. Represa, Y. Ben-Ari, and R. Cossart. 2009. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks. Science 326: 1419–1424.

    Article  CAS  PubMed  Google Scholar 

  15. Borders, E.B., C. Bivona, and P.J. Medina. 2010. Mammalian target of rapamycin: Biological function and target for novel anticancer agents. American Journal of Health-System Pharmacy 67: 2095–2106.

    Article  CAS  PubMed  Google Scholar 

  16. Borgert, C.J., T.F. Quill, L.S. Mccarty, and A.M. Mason. 2004. Can mode of action predict mixture toxicity for risk assessment? Toxicology and Applied Pharmacology 201: 85–96.

    Article  CAS  PubMed  Google Scholar 

  17. Bottino, D., R.C. Penland, A. Stamps, M. Traebert, B. Dumotier, A. Georgiva, G. Helmlinger, and G.S. Lett. 2006. Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart. Progress in Biophysics and Molecular Biology 90: 414–443.

    Article  CAS  PubMed  Google Scholar 

  18. Calabrese, C., H. Poppleton, M. Kocak, T.L. Hogg, C. Fuller, B. Hamner, E.Y. Oh, M.W. Gaber, D. Finklestein, M. Allen, A. Frank, I.T. Bayazitov, S.S. Zakharenko, A. Gajjar, A. Davidoff, and R.J. Gilbertson. 2007. A perivascular niche for brain tumor stem cells. Cancer Cell 11: 69–82.

    Article  CAS  PubMed  Google Scholar 

  19. Calvisi, D.F., S. Ladu, A. Gorden, M. Farina, E.A. Conner, J.S. Lee, V.M. Factor, and S.S. Thorgeirsson. 2006. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130: 1117–1128.

    Article  CAS  PubMed  Google Scholar 

  20. Cardenas, M.E., A. Sanfridson, N.S. Cutler, and J. Heitman. 1998. Signal-transduction cascades as targets for therapeutic intervention by natural products. Trends in Biotechnology 16: 427–433.

    Article  CAS  PubMed  Google Scholar 

  21. Chan, S.L., A.M. Wong, K. Lee, N. Wong, and A.K. Chan. 2016. Personalized therapy for hepatocellular carcinoma: Where are we now? Cancer Treatment Reviews 45: 77–86.

    Article  PubMed  Google Scholar 

  22. Chang, W., A.S. Brohl, R. Patidar, S. Sindiri, J.F. Shern, J.S. Wei, Y.K. Song, M.E. Yohe, B. Gryder, S. Zhang, K.A. Calzone, N. Shivaprasad, X. Wen, T.C. Badgett, M. Miettinen, K.R. Hartman, J.C. League-Pascual, T.N. Trahair, B.C. Widemann, M.S. Merchant, R.N. Kaplan, J.C. Lin, and J. Khan. 2016. 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 22: 3810–3820.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chen, X., H. Zhou, Y.B. Liu, J.F. Wang, H. Li, C.Y. Ung, L.Y. Han, Z.W. Cao, and Y.Z. Chen. 2006. Database of traditional Chinese medicine and its application to studies of mechanism and to prescription validation. British Journal of Pharmacology 149: 1092–1103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, R.J., Y.S. Ho, H.R. Guo, and Y.J. Wang. 2008. Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. Toxicological Sciences 104: 283–293.

    Article  CAS  PubMed  Google Scholar 

  25. Cheng, X., J. Huo, D. Wang, X. Cai, X. Sun, W. Lu, Y. Yang, C. Hu, X. Wang, and P. Cao. 2017. Herbal medicine Ac591 prevents oxaliplatin-induced peripheral neuropathy in animal model and cancer patients. Frontiers in Pharmacology 8: 344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Corbin, J.D., A. Beasley, M.A. Blount, and S.H. Francis. 2005. High lung PDE5: A strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochemical and Biophysical Research Communications 334: 930–938.

    Article  CAS  PubMed  Google Scholar 

  27. Cragg, G.M., D.J. Newman, and R.B. Weiss. 1997. Coral reefs, forests, and thermal vents: The worldwide exploration of nature for novel antitumor agents. Seminars in Oncology 24: 156–163.

    CAS  PubMed  Google Scholar 

  28. Da Rocha, A.B., R.M. Lopes, and G. Schwartsmann. 2001. Natural products in anticancer therapy. Current Opinion in Pharmacology 1: 364–369.

    Article  PubMed  Google Scholar 

  29. Dassa, E., and P. Bouige. 2001. The ABC of ABCs: A phylogenetic and functional classification of ABC systems in living organisms. Research in Microbiology 152: 211–229.

    Article  CAS  PubMed  Google Scholar 

  30. Dawood, M., S. Hamdoun, and T. Efferth. 2018. Multifactorial modes of action of arsenic trioxide in cancer cells as analyzed by classical and network pharmacology. Frontiers in Pharmacology 9: 143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. De Araujo, V.C., C. Furuse, P.R. Cury, A. Altemani, and N.S. De Araujo. 2008. STAT3 expression in salivary gland tumours. Oral Oncology 44: 439–445.

    Article  PubMed  CAS  Google Scholar 

  32. De, O., and B. Prasun Chatterji. 2017. Marine derived anticancer drugs targeting microtubule. Recent Patents on Anti-Cancer Drug Discovery 12 (2): 102–127.

    Article  CAS  PubMed  Google Scholar 

  33. Demain, A.L., and P. Vaishnav. 2011. Natural products for cancer chemotherapy. Microbial Biotechnology 4: 687–699.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Derosa, G., D. Romano, A. D’angelo, and P. Maffioli. 2015. Berberis aristata/Silybum marianum fixed combination (Berberol(R)) effects on lipid profile in dyslipidemic patients intolerant to statins at high dosages: A randomized, placebo-controlled, clinical trial. Phytomedicine 22: 231–237.

    Article  PubMed  Google Scholar 

  35. Dimasi, J.A., L. Feldman, A. Seckler, and A. Wilson. 2010. Trends in risks associated with new drug development: Success rates for investigational drugs. Clinical Pharmacology and Therapeutics 87: 272–277.

    Article  CAS  PubMed  Google Scholar 

  36. Dimasi, J.A., H.G. Grabowski, and R.W. Hansen. 2016. Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics 47: 20–33.

    Article  PubMed  Google Scholar 

  37. Dopazo, J. 2014. Genomics and transcriptomics in drug discovery. Drug Discovery Today 19: 126–132.

    Article  CAS  PubMed  Google Scholar 

  38. Dumontet, C., and M.A. Jordan. 2010. Microtubule-binding agents: A dynamic field of cancer therapeutics. Nature Reviews. Drug Discovery 9: 790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Durrant, J.D., and J.A. Mccammon. 2011. Molecular dynamics simulations and drug discovery. BMC Biology 9: 71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Efferth, T. 2012. Stem cells, cancer stem-like cells, and natural products. Planta Medica 78: 935–942.

    Article  CAS  PubMed  Google Scholar 

  41. ———. 2014. Resistance to targeted ABC transporters in cancer. New York: Springer.

    Google Scholar 

  42. Efferth, T., and H.J. Greten. 2012. In silico analysis of microarray-based gene expression profiles predicts tumor cell response to withanolides. Microarrays (Basel) 1: 44–63.

    Article  CAS  Google Scholar 

  43. Efferth, T., and M. Volm. 2005. Pharmacogenetics for individualized cancer chemotherapy. Pharmacology & Therapeutics 107: 155–176.

    Article  CAS  Google Scholar 

  44. Efferth, T., Y.J. Fu, Y.G. Zu, G. Schwarz, V.S. Konkimalla, and M. Wink. 2007a. Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Current Medicinal Chemistry 14: 2024–2032.

    Article  CAS  PubMed  Google Scholar 

  45. Efferth, T., H. Miyachi, and H. Bartsch. 2007b. Pharmacogenomics of a traditional Japanese herbal medicine (Kampo) for cancer therapy. Cancer Genomics Proteomics 4: 81–91.

    CAS  PubMed  Google Scholar 

  46. Efferth, T., S. Kahl, K. Paulus, M. Adams, R. Rauh, H. Boechzelt, X. Hao, B. Kaina, and R. Bauer. 2008a. Phytochemistry and pharmacogenomics of natural products derived from traditional Chinese medicine and Chinese Materia Medica with activity against tumour cells. Molecular Cancer Therapeutics 7 (1): 152–161.

    Article  CAS  PubMed  Google Scholar 

  47. Efferth, T., V.B. Konkimalla, Y.-F. Wang, A. Sauerbrey, S. Meinhardt, F. Zintl, J. Mattern, and M. Volm. 2008b. Prediction of broad spectrum resistance of tumors towards anticancer drugs. Clinical Cancer Research 14: 2405–2412.

    Article  CAS  PubMed  Google Scholar 

  48. Efferth, T., M.E.M. Saeed, E. Mirghani, A. Alim, Z. Yassin, E. Saeed, H.E. Khalid, and S. Daak. 2017. Integration of phytochemicals and phytotherapy into cancer precision medicine. Oncotarget 8: 50284–50304.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Efferth, T., M. Banerjee, M.S. Abu-Darwish, S. Abdelfatah, M. Böckers, D. Bhakta-Guha, V. Bolzani, S. Daak, Ö.L. Demirezer, M. Dawood, M. Efferth, H.R. El-Seedi, N. Fischer, H.J. Greten, S. Hamdoun, C. Hong, M. Horneber, O. Kadioglu, H.E. Khalid, S.A. Khalid, V. Kuete, N. Mahmoud, J. Marin, A. Mbaveng, J. Midiwo, H. Nakagawa, J. Nas, O. Ngassapa, D. Ochwang’i, L.K. Omosa, E.A. Ooko, N. Özenver, P. Poornima, M.R. Romero, M.E.M. Saeed, L. Salgueiro, E.-J. Seo, G. Yan, Z. Yasin, E.M. Saeed, and N.W. Paul. 2019. Biopiracy versus one-world medicine–from colonial relicts to global collaborative concepts. Phytomedicine 53: 319–331.

    Article  PubMed  Google Scholar 

  50. English, A.C., S. Richards, Y. Han, M. Wang, V. Vee, J. Qu, X. Qin, D.M. Muzny, J.G. Reid, and K.C. Worley. 2012. Mind the gap: upgrading genomes with Pacific Biosciences RS long-read sequencing technology. PLoS One 7: e47768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fan, W. 2001. The Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS) and its application. INSPEL 35 (3): 147–156.

    Google Scholar 

  52. Gennemark, P., and D. Wedelin. 2007. Efficient algorithms for ordinary differential equation model identification of biological systems. IET Systems Biology 1: 120–129.

    Article  CAS  PubMed  Google Scholar 

  53. Gerlinger, M., A.J. Rowan, S. Horswell, J. Larkin, D. Endesfelder, E. Gronroos, P. Martinez, N. Matthews, A. Stewart, P. Tarpey, I. Varela, B. Phillimore, S. Begum, N.Q. Mcdonald, A. Butler, D. Jones, K. Raine, C. Latimer, C.R. Santos, M. Nohadani, A.C. Eklund, B. Spencer-Dene, G. Clark, L. Pickering, G. Stamp, M. Gore, Z. Szallasi, J. Downward, P.A. Futreal, and C. Swanton. 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine 366: 883–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gillet, J.P., T. Efferth, and J. Remacle. 2007. Chemotherapy-induced resistance by ATP-binding cassette transporter genes. Biochimica et Biophysica Acta 1775: 237–262.

    CAS  PubMed  Google Scholar 

  55. Gonzalez-Angulo, A.M., B.T.J. Hennessy, and G.B. Mills. 2010. Future of personalized medicine in oncology: A systems biology approach. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28: 2777–2783.

    Article  CAS  Google Scholar 

  56. Gordaliza, M. 2007. Natural products as leads to anticancer drugs. Clinical & Translational Oncology 9: 767–776.

    Article  CAS  Google Scholar 

  57. Gosak, M., R. Markovic, A. Fajmut, M. Marhl, M. Hawlina, and S. Andjelic. 2015. The analysis of intracellular and intercellular calcium signaling in human anterior lens capsule epithelial cells with regard to different types and stages of the cataract. PLoS One 10: e0143781.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Gosak, M., R. Markovič, J. Dolenšek, M. Slak Rupnik, M. Marhl, A. Stožer, and M. Perc. 2018. Network science of biological systems at different scales: A review. Physics of Life Reviews 24: 118–135.

    Article  PubMed  Google Scholar 

  59. Govindarajan, R., J. Duraiyan, K. Kaliyappan, and M. Palanisamy. 2012. Microarray and its applications. Journal of Pharmacy & Bioallied Sciences 4: S310–S312.

    Article  CAS  Google Scholar 

  60. Grivennikov, S.I., and M. Karin. 2010. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine & Growth Factor Reviews 21: 11–19.

    Article  CAS  Google Scholar 

  61. Gu, S., and J. Pei. 2017. Chinese herbal medicine meets biological networks of complex diseases: A computational perspective. Evidence-based Complementary and Alternative Medicine 2017: 7198645.

    PubMed  PubMed Central  Google Scholar 

  62. Gu, H., L. Ma, Y. Ren, W. He, Y. Wang, and Y. Qiao. 2014a. Exploration of the mechanism of pattern-specific treatments in coronary heart disease with network pharmacology approach. Computers in Biology and Medicine 51: 198–204.

    Article  PubMed  Google Scholar 

  63. Gu, S., D.-A. Silva, L. Meng, A. Yue, and X. Huang. 2014b. Quantitatively characterizing the ligand binding mechanisms of choline binding protein using Markov state model analysis. PLoS Computational Biology 10: e1003767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Guo, L., Q. Li, Q. Xia, S. Dial, P.-C. Chan, and P. Fu. 2009. Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract. Food and Chemical Toxicology 47: 433–442.

    Article  CAS  PubMed  Google Scholar 

  65. Guo, L., N. Mei, W. Liao, P.C. Chan, and P.P. Fu. 2010a. Ginkgo biloba extract induces gene expression changes in xenobiotics metabolism and the Myc-centered network. OMICS 14: 75–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Guo, L., N. Mei, Q. Xia, T. Chen, P.C. Chan, and P.P. Fu. 2010b. Gene expression profiling as an initial approach for mechanistic studies of toxicity and tumorigenicity of herbal plants and herbal dietary supplements. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews 28: 60–87.

    Article  CAS  Google Scholar 

  67. Hartmann, J.T., and H.P. Lipp. 2006. Camptothecin and podophyllotoxin derivatives: Inhibitors of topoisomerase I and II – mechanisms of action, pharmacokinetics and toxicity profile. Drug Safety 29: 209–230.

    Article  CAS  PubMed  Google Scholar 

  68. Harvey, A.L. 1999. Medicines from nature: Are natural products still relevant to drug discovery? Trends in Pharmacological Sciences 20: 196–198.

    Article  CAS  PubMed  Google Scholar 

  69. Hirano, T., K. Ishihara, and M. Hibi. 2000. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19: 2548–2556.

    Article  CAS  PubMed  Google Scholar 

  70. Holohan, C., S. Van Schaeybroeck, D.B. Longley, and P.G. Johnston. 2013. Cancer drug resistance: An evolving paradigm. Nature Reviews. Cancer 13: 714–726.

    Article  CAS  PubMed  Google Scholar 

  71. Hong, C., J. Cao, C.F. Wu, O. Kadioglu, A. Schuffler, U. Kauhl, S.M. Klauck, T. Opatz, E. Thines, N.W. Paul, and T. Efferth. 2017. The Chinese herbal formula Free and Easy Wanderer ameliorates oxidative stress through KEAP1-NRF2/HO-1 pathway. Scientific Reports 7: 11551.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Hopkins, A.L. 2008. Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology 4: 682–690.

    Article  CAS  PubMed  Google Scholar 

  73. Huang, L., D. Xie, Y. Yu, H. Liu, Y. Shi, T. Shi, and C. Wen. 2018. TCMID 2.0: A comprehensive resource for TCM. Nucleic Acids Research 46: D1117–d1120.

    Article  CAS  PubMed  Google Scholar 

  74. Hunter, P., V. Coveney Peter, B. De Bono, V. Diaz, J. Fenner, F. Frangi Alejandro, P. Harris, R. Hose, P. Kohl, P. Lawford, K. Mccormack, M. Mendes, S. Omholt, A. Quarteroni, J. Skår, J. Tegner, S. Randall Thomas, I. Tollis, I. Tsamardinos, H.G.M. Van Beek Johannes, and M. Viceconti. 2010. A vision and strategy for the virtual physiological human in 2010 and beyond. Philosophical Transactions of the Royal Society A – Mathematical Physical and Engineering Sciences 368: 2595–2614.

    Article  Google Scholar 

  75. Kadioglu, O., and T. Efferth. 2015. Pharmacogenomic characterization of cytotoxic compounds from salvia officinalis in cancer cells. Journal of Natural Products 78: 762–775.

    Article  CAS  PubMed  Google Scholar 

  76. Kadioglu, O., N.S. Kermani, G. Kelter, U. Schumacher, H.H. Fiebig, H.J. Greten, and T. Efferth. 2014. Pharmacogenomics of cantharidin in tumor cells. Biochemical Pharmacology 87: 399–409.

    Article  CAS  PubMed  Google Scholar 

  77. Kadioglu, O., M. Saeed, V. Kuete, H.J. Greten, and T. Efferth. 2018. Oridonin targets multiple drug-resistant tumor cells as determined by in silico and in vitro analyses. Frontiers in Pharmacology 9: 355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Kalimuthu, S., and K. Se-Kwon. 2013. Cell survival and apoptosis signaling as therapeutic target for cancer: Marine bioactive compounds. International Journal of Molecular Sciences 14: 2334–2354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kasinski, A.L., Y. Du, S.L. Thomas, J. Zhao, S.Y. Sun, F.R. Khuri, C.Y. Wang, M. Shoji, A. Sun, J.P. Snyder, D. Liotta, and H. Fu. 2008. Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin. Molecular Pharmacology 74: 654–661.

    Article  CAS  PubMed  Google Scholar 

  80. Kitano, H. 2002. Computational systems biology. Nature 420: 206–210.

    Article  CAS  PubMed  Google Scholar 

  81. Koch-Weser, J., and P.J. Schechter. 1978. Schmiedeberg in Strassburg 1872–1918: The making of modern pharmacology. Life Sciences 22: 1361–1371.

    Article  CAS  PubMed  Google Scholar 

  82. Kohl, P., and D. Noble. 2009. Systems biology and the virtual physiological human. Molecular Systems Biology 5: 292.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kola, I., and J. Landis. 2004. Can the pharmaceutical industry reduce attrition rates? Nature Reviews. Drug Discovery 3: 711.

    Article  CAS  PubMed  Google Scholar 

  84. Konkimalla, V., V. Suhas, N. Chandra, E. Gebhart, and T. Efferth. 2007. From molecular diagnostics to molecular targeted therapy with natural product small molecule inhibitors in oral squamous cell carcinoma. Planta Medica 73 (9): 4.

    Article  Google Scholar 

  85. Kresty, L.A., S.R. Mallery, and G.D. Stoner. 2016. Black raspberries in cancer clinical trials: Past, present and future. Journal of Berry Research 6: 251–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kuete, V., and T. Efferth. 2011. Pharmacogenomics of Cameroonian traditional herbal medicine for cancer therapy. Journal of Ethnopharmacology 137: 752–766.

    Article  PubMed  Google Scholar 

  87. Kuete, V., M.E. Saeed, O. Kadioglu, J. Börtzler, H. Khalid, H.J. Greten, and T. Efferth. 2015. Pharmacogenomic and molecular docking studies on the cytotoxicity of the natural steroid wortmannin against multidrug-resistant tumor cells. Phytomedicine 22: 120–127.

    Article  CAS  PubMed  Google Scholar 

  88. Lage, H. 2003. ABC-transporters: Implications on drug resistance from microorganisms to human cancers. International Journal of Antimicrobial Agents 22: 188–199.

    Article  CAS  PubMed  Google Scholar 

  89. Lam, W., S. Bussom, F. Guan, Z. Jiang, W. Zhang, E.A. Gullen, S.H. Liu, and Y.C. Cheng. 2010. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Science Translational Medicine 2 (45): 45ra59.

    Article  PubMed  CAS  Google Scholar 

  90. Lamb, J., E.D. Crawford, D. Peck, J.W. Modell, I.C. Blat, M.J. Wrobel, J. Lerner, J.P. Brunet, A. Subramanian, K.N. Ross, M. Reich, H. Hieronymus, G. Wei, S.A. Armstrong, S.J. Haggarty, P.A. Clemons, R. Wei, S.A. Carr, E.S. Lander, and T.R. Golub. 2006. The connectivity map: Using gene-expression signatures to connect small molecules, genes, and disease. Science 313: 1929–1935.

    Article  CAS  PubMed  Google Scholar 

  91. Leary, R.J., J.C. Lin, J. Cummins, S. Boca, L.D. Wood, D.W. Parsons, S. Jones, T. Sjoblom, B.H. Park, R. Parsons, J. Willis, D. Dawson, J.K. Willson, T. Nikolskaya, Y. Nikolsky, L. Kopelovich, N. Papadopoulos, L.A. Pennacchio, T.L. Wang, S.D. Markowitz, G. Parmigiani, K.W. Kinzler, B. Vogelstein, and V.E. Velculescu. 2008. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proceedings of the National Academy of Sciences of the United States of America 105: 16224–16229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, S. 2015. Systems biology – a pivotal research methodology for understanding the mechanisms of traditional medicine. Journal of Pharmacopuncture 18: 11–18.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Lee, J.-H., K.M. Park, D.-J. Han, N.Y. Bang, D.-H. Kim, H. Na, S. Lim, T.B. Kim, D.G. Kim, H.-J. Kim, Y. Chung, S.H. Sung, Y.-J. Surh, S. Kim, and B.W. Han. 2015. PharmDB-K: Integrated bio-pharmacological network database for traditional Korean medicine. PLoS One 10: e0142624–e0142624.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Li, Z., and C. Xu. 2011. The fundamental theory of traditional Chinese medicine and the consideration in its research strategy. Frontiers in Medicine 5: 208–211.

    Article  Google Scholar 

  95. Li, S., and B. Zhang. 2013. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chinese Journal of Natural Medicines 11: 110–120.

    Article  PubMed  Google Scholar 

  96. Li, H., Z. Gao, L. Kang, H. Zhang, K. Yang, K. Yu, X. Luo, W. Zhu, K. Chen, J. Shen, X. Wang, and H. Jiang. 2006. TarFisDock: A web server for identifying drug targets with docking approach. Nucleic Acids Research 34: W219–W224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li, W.F., J.G. Jiang, and J. Chen. 2008. Chinese medicine and its modernization demands. Archives of Medical Research 39: 246–251.

    Article  PubMed  Google Scholar 

  98. Li, S., B. Zhang, D. Jiang, Y. Wei, and N. Zhang. 2010. Herb network construction and co-module analysis for uncovering the combination rule of traditional Chinese herbal formulae. BMC Bioinformatics 11: S6.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Li, Z., T. Qin, K. Wang, M. Hackenberg, J. Yan, Y. Gao, L.-R. Yu, L. Shi, Z. Su, and T. Chen. 2015. Integrated microRNA, mRNA, and protein expression profiling reveals microRNA regulatory networks in rat kidney treated with a carcinogenic dose of aristolochic acid. BMC Genomics 16: 365.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Lin, L.L., C.R. Hsia, C.L. Hsu, H.C. Huang, and H.F. Juan. 2015. Integrating transcriptomics and proteomics to show that tanshinone IIA suppresses cell growth by blocking glucose metabolism in gastric cancer cells. BMC Genomics 16: 41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Liu, L.F. 1989. DNA topoisomerase poisons as antitumor drugs. Annual Review of Biochemistry 58: 351–375.

    Article  CAS  PubMed  Google Scholar 

  102. Liu, L.F., S.D. Desai, T.K. Li, Y. Mao, M. Sun, and S.P. Sim. 2000. Mechanism of action of camptothecin. Annals of the New York Academy of Sciences 922: 1–10.

    Article  CAS  PubMed  Google Scholar 

  103. Liu, L., Y. Li, S. Li, N. Hu, Y. He, R. Pong, D. Lin, L. Lu, and M. Law. 2012. Comparison of next-generation sequencing systems. BioMed Research International 2012: 251364.

    Google Scholar 

  104. Liu, H., J. Wang, W. Zhou, Y. Wang, and L. Yang. 2013. Systems approaches and polypharmacology for drug discovery from herbal medicines: An example using licorice. Journal of Ethnopharmacology 46: 773–793.

    Article  CAS  Google Scholar 

  105. Loganathan, J., J. Jiang, A. Smith, A. Jedinak, A. Thyagarajan-Sahu, G.E. Sandusky, H. Nakshatri, and D. Sliva. 2014. The mushroom Ganoderma lucidum suppresses breast-to-lung cancer metastasis through the inhibition of pro-invasive genes. International Journal of Oncology 44: 2009–2015.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Luckner, M. 2013. Secondary metabolism in microorganisms, plants and animals. Berlin/Heidelberg: Springer.

    Google Scholar 

  107. Lukman, S., Y. He, and S.-C. Hui. 2007. Computational methods for traditional Chinese medicine: A survey. Computer Methods and Programs in Biomedicine 88: 283–294.

    Article  PubMed  Google Scholar 

  108. Ma, L., B. Wang, Y. Long, and H. Li. 2017. Effect of traditional Chinese medicine combined with Western therapy on primary hepatic carcinoma: A systematic review with meta-analysis. Frontiers in Medicine 11: 191–202.

    Article  Google Scholar 

  109. Malmersjö, S., P. Rebellato, E. Smedler, H. Planert, S. Kanatani, I. Liste, E. Nanou, H. Sunner, S. Abdelhady, and S. Zhang. 2013. Neural progenitors organize in small-world networks to promote cell proliferation. Proceedings of the National Academy of Sciences 110 (16): E1524–E1532.

    Article  Google Scholar 

  110. Mao, J.J., S.X. Xie, J. Zee, I. Soeller, Q.S. Li, K. Rockwell, and J.D. Amsterdam. 2015. Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. Phytomedicine 22: 394–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Margulies, M., M. Egholm, W.E. Altman, S. Attiya, J.S. Bader, L.A. Bemben, J. Berka, M.S. Braverman, Y.J. Chen, Z. Chen, S.B. Dewell, L. Du, J.M. Fierro, X.V. Gomes, B.C. Godwin, W. He, S. Helgesen, C.H. Ho, G.P. Irzyk, S.C. Jando, M.L. Alenquer, T.P. Jarvie, K.B. Jirage, J.B. Kim, J.R. Knight, J.R. Lanza, J.H. Leamon, S.M. Lefkowitz, M. Lei, J. Li, K.L. Lohman, H. Lu, V.B. Makhijani, K.E. Mcdade, M.P. Mckenna, E.W. Myers, E. Nickerson, J.R. Nobile, R. Plant, B.P. Puc, M.T. Ronan, G.T. Roth, G.J. Sarkis, J.F. Simons, J.W. Simpson, M. Srinivasan, K.R. Tartaro, A. Tomasz, K.A. Vogt, G.A. Volkmer, S.H. Wang, Y. Wang, M.P. Weiner, P. Yu, R.F. Begley, and J.M. Rothberg. 2005. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437: 376–380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Markovič, R., A. Stožer, M. Gosak, J. Dolenšek, M. Marhl, and M.S. Rupnik. 2015. Progressive glucose stimulation of islet beta cells reveals a transition from segregated to integrated modular functional connectivity patterns. Scientific Reports 5: 7845.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Mason, O., and M. Verwoerd. 2007. Graph theory and networks in biology. IET Systems Biology 1: 89–119.

    Article  CAS  PubMed  Google Scholar 

  114. Maulik, S.K., V. Wilson, S. Seth, B. Bhargava, P. Dua, S. Ramakrishnan, and C.K. Katiyar. 2016. Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb. ex DC.) Wight & Arn. in patients of chronic heart failure: a double-blind, randomized controlled trial. Phytomedicine 23: 1211–1219.

    Article  PubMed  Google Scholar 

  115. Maxam, A.M., and W. Gilbert. 1977. A new method for sequencing DNA. Proceedings of the National Academy of Sciences of the United States of America 74: 560–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Meacham, C.E., and S.J. Morrison. 2013. Tumour heterogeneity and cancer cell plasticity. Nature 501: 328–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Miao, X., and Q.L.X. Qin. 2015. Genome-wide transcriptome analysis of mRNAs and microRNAs in Dorset and Small Tail Han sheep to explore the regulation of fecundity. Molecular and Cellular Endocrinology 402: 32–42.

    Article  CAS  PubMed  Google Scholar 

  118. Mikheyev, A.S., and M.M. Tin. 2014. A first look at the Oxford Nanopore MinION sequencer. Molecular Ecology Resources 14: 1097–1102.

    Article  CAS  PubMed  Google Scholar 

  119. Moeller, B.J., R. Pasqualini, and W. Arap. 2009. Targeting cancer-specific synthetic lethality in double-strand DNA break repair. Cell Cycle 8: 1872–1876.

    Article  CAS  PubMed  Google Scholar 

  120. Mohs, R.C., and N.H. Greig. 2017. Drug discovery and development: Role of basic biological research. Alzheimers Dement (NY) 3: 651–657.

    Google Scholar 

  121. Mullard, A. 2018. 2017 FDA drug approvals. Nature Reviews Drug Discovery 17: 81.

    Article  CAS  PubMed  Google Scholar 

  122. Munakata, K., K. Takashima, M. Nishiyama, N. Asano, A. Mase, K. Hioki, Y. Ohnishi, M. Yamamoto, and K. Watanabe. 2012. Microarray analysis on germfree mice elucidates the primary target of a traditional Japanese medicine juzentaihoto: Acceleration of IFN-alpha response via affecting the ISGF3-IRF7 signaling cascade. BMC Genomics 13: 30.

    Article  PubMed  PubMed Central  Google Scholar 

  123. National Cancer Institute. 2019. Cancer statistics, viewed 4 January 2019. https://www.cancer.gov/about-cancer/understanding/statistics

  124. National Institutes of Health. 2019. Computational modeling, viewed 9 Ferbruary 2019. https://www.nibib.nih.gov/science-education/science-topics/computational-modeling

  125. National Toxicology Program U.S. Department of Health and Human Service. 2019. About the report on carcinogens, viewed 6 February 2019. https://ntp.niehs.nih.gov/pubhealth/roc/index.html.

  126. Naveen, C.R., S. Gaikwad, and R. Agrawal-Rajput. 2016. Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells. Phytomedicine 23: 736–744.

    Article  CAS  PubMed  Google Scholar 

  127. Naveja, J.J., A. Dueñas-González, and J.L. Medina-Franco. 2016. Drug repurposing for epigenetic targets guided by computational methods. In Epi-informatics, ed. J.L. Medina-Franco. Boston: Academic Press.

    Google Scholar 

  128. Newman, D.J., and G.M. Cragg. 2016. Natural products as sources of new drugs from 1981 to 2014. Journal of Natural Products 79: 629–661.

    Article  CAS  PubMed  Google Scholar 

  129. Nisbet, R., G. Miner, and K. Yale. 2018. Theoretical considerations for data mining. In Handbook of statistical analysis and data mining applications, ed. R. Nisbet, G. Miner, and K. Yale, 2nd ed. Boston: Academic Press.

    Google Scholar 

  130. Noble, D. 1962. A modification of the Hodgkin-Huxley equations applicable to Purkinje fibre action and pace-maker potentials. The Journal of Physiology 160: 317–352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Noble, R.L. 1990. The discovery of the vinca alkaloids–chemotherapeutic agents against cancer. Biochemistry and Cell Biology 68: 1344–1351.

    Article  CAS  PubMed  Google Scholar 

  132. Nowell, P.C. 1976. The clonal evolution of tumor cell populations. Science 194: 23–28.

    Article  CAS  PubMed  Google Scholar 

  133. Nygren, P., and R. Larsson. 2014. Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncologica 53: 427–428.

    Article  PubMed  Google Scholar 

  134. Ojima, I., S. Chakravarty, T. Inoue, S. Lin, L. He, S.B. Horwitz, S.D. Kuduk, and S.J. Danishefsky. 1999. A common pharmacophore for cytotoxic natural products that stabilize microtubules. Proceedings of the National Academy of Sciences of the United States of America 96: 4256–4261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Omosa, L.K., J.O. Midiwo, V.M. Masila, B.M. Gisacho, R. Munayi, K. Francisca, K.P. Chemutai, G. Elhaboob, M.E. Saeed, S. Hamdoun, V. Kuete, and T. Efferth. 2016. Cytotoxicity of 91 Kenyan indigenous medicinal plants towards human CCRF-CEM leukemia cells. Journal of Ethnopharmacology 179: 177–196.

    Article  CAS  PubMed  Google Scholar 

  136. Ooko, E., O. Kadioglu, H.J. Greten, and T. Efferth. 2017. Pharmacogenomic characterization and isobologram analysis of the combination of ascorbic acid and curcumin-two main metabolites of curcuma longa-in cancer cells. Frontiers in Pharmacology 8: 38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Ouyang, L., Y. Luo, M. Tian, S.Y. Zhang, R. Lu, J.H. Wang, R. Kasimu, and X. Li. 2014. Plant natural products: From traditional compounds to new emerging drugs in cancer therapy. Cell Proliferation 47: 506–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ovadje, P., A. Roma, M. Steckle, L. Nicoletti, J.T. Arnason, and S. Pandey. 2015. Advances in the research and development of natural health products as main stream cancer therapeutics. Evidence-based Complementary and Alternative Medicine 2015: 751348.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Özenver, N., M. Saeed, L.Ö. Demirezer, and T. Efferth. 2018. Aloe-emodin as drug candidate for cancer therapy. Oncotarget 9: 17770–17796.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Pantziarka, P., G. Bouche, L. Meheus, V. Sukhatme, and V.P. Sukhatme. 2014. Repurposing drugs in oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedical Science 8: 443–443.

    Google Scholar 

  141. Pantziarka, P., M. Pirmohamed, and N. Mirza. 2018. New uses for old drugs. British Medical Journal 361: k2701.

    Article  PubMed  Google Scholar 

  142. Park, I.H., and C. Li. 2011. Characterization of molecular recognition of STAT3 SH2 domain inhibitors through molecular simulation. Journal of Molecular Recognition 24: 254–265.

    Article  CAS  PubMed  Google Scholar 

  143. Pfisterer, P.H., G. Wolber, T. Efferth, J.M. Rollinger, and H. Stuppner. 2010. Natural products in structure-assisted design of molecular cancer therapeutics. Current Pharmaceutical Design 16: 1718–1741.

    Article  CAS  PubMed  Google Scholar 

  144. Pinedo, H.M., G. Giaccone, and K. Sikora. 2007. Drug resistance in the treatment of cancer. Cambridge: Cambridge University Press.

    Google Scholar 

  145. Pineo, D., and C. Ware. 2012. Data visualization optimization via computational modeling of perception. IEEE Transactions on Visualization and Computer Graphics 18: 309–320.

    Article  PubMed  Google Scholar 

  146. Poornima, P., J.D. Kumar, Q. Zhao, M. Blunder, and T. Efferth. 2016. Network pharmacology of cancer: from understanding of complex interactomes to the design of multi-target specific therapeutics from nature. Pharmacological Research 111: 290–302.

    Article  CAS  PubMed  Google Scholar 

  147. Priya, R., R. Sumitha, C.G.P. Doss, C. Rajasekaran, S. Babu, R. Seenivasan, and R. Siva. 2015. Molecular docking and molecular dynamics to identify a novel human immunodeficiency virus inhibitor from alkaloids of Toddalia asiatica. Pharmacognosy Magazine 11: S414–S422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Quanquan, G., and R. Tingge. 2009. An improved mathematic model of relative dosage of herb for Chinese medicine prescription. Ori-ental Journal of Mathematics 1: 13–25.

    Google Scholar 

  149. Quarteroni, A. 2018. ‘The role of statistics in the era of big data: a computational scientist’ perspective. Statistics & Probability Letters 136: 63–67.

    Article  Google Scholar 

  150. Quintana, E., M. Shackleton, H.R. Foster, D.R. Fullen, M.S. Sabel, T.M. Johnson, and S.J. Morrison. 2010. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18: 510–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Reddy, L., B. Odhav, and K.D. Bhoola. 2003. Natural products for cancer prevention: A global perspective. Pharmacology & Therapeutics 99: 1–13.

    Article  CAS  Google Scholar 

  152. Resemann, H.K., C.J. Watson, and B. Lloyd-Lewis. 2014. The Stat3 paradox: A killer and an oncogene. Molecular and Cellular Endocrinology 382: 603–611.

    Article  CAS  PubMed  Google Scholar 

  153. Rocha-Martin, J., C. Harrington, A.D. Dobson, and F. O’gara. 2014. Emerging strategies and integrated systems microbiology technologies for biodiscovery of marine bioactive compounds. Marine Drugs 12: 3516–3559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Rodriguez, B., K. Burrage, D. Gavaghan, V. Grau, P. Kohl, and D. Noble. 2010. The systems biology approach to drug development: Application to toxicity assessment of cardiac drugs. Clinical Pharmacology and Therapeutics 88: 130–134.

    Article  CAS  PubMed  Google Scholar 

  155. Rothberg, J.M., W. Hinz, T.M. Rearick, J. Schultz, W. Mileski, M. Davey, J.H. Leamon, K. Johnson, M.J. Milgrew, M. Edwards, J. Hoon, J.F. Simons, D. Marran, J.W. Myers, J.F. Davidson, A. Branting, J.R. Nobile, B.P. Puc, D. Light, T.A. Clark, M. Huber, J.T. Branciforte, I.B. Stoner, S.E. Cawley, M. Lyons, Y. Fu, N. Homer, M. Sedova, X. Miao, B. Reed, J. Sabina, E. Feierstein, M. Schorn, M. Alanjary, E. Dimalanta, D. Dressman, R. Kasinskas, T. Sokolsky, J.A. Fidanza, E. Namsaraev, K.J. Mckernan, A. Williams, G.T. Roth, and J. Bustillo. 2011. An integrated semiconductor device enabling non-optical genome sequencing. Nature 475: 348.

    Article  CAS  PubMed  Google Scholar 

  156. Sadzuka, Y., T. Sugiyama, K. Shimoi, N. Kinae, and S. Hirota. 1997. Protective effect of flavonoids on doxorubicin-induced cardiotoxicity. Toxicology Letters 92: 1–7.

    Article  CAS  PubMed  Google Scholar 

  157. Saeed, M., H. Khalid, Y. Sugimoto, and T. Efferth. 2014. The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: Pharmacogenomic determination of genes associated with sensitivity or resistance. Phytomedicine 21: 689–696.

    Article  CAS  PubMed  Google Scholar 

  158. Saeed, M., O. Kadioglu, H. Khalid, Y. Sugimoto, and T. Efferth. 2015. Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking. The Journal of Nutritional Biochemistry 26: 44–56.

    Article  CAS  PubMed  Google Scholar 

  159. Saeed, M.E., M. Meyer, A. Hussein, and T. Efferth. 2016. Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells. Journal of Ethnopharmacology 186: 209–223.

    Article  CAS  PubMed  Google Scholar 

  160. Saeed, M.E.M., N. Mahmoud, Y. Sugimoto, T. Efferth, and H. Abdel-Aziz. 2018a. Betulinic acid exerts cytotoxic activity against multidrug-resistant tumor cells via targeting autocrine motility factor receptor (AMFR). Frontiers in Pharmacology 9: 481.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. ———. 2018b. Molecular determinants of sensitivity or resistance of cancer cells toward sanguinarine. Frontiers in Pharmacology 9: 136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Sanger, F., S. Nicklen, and A.R. Coulson. 1977. DNA sequencing with chain-terminating inhibitors. Proceedings the National Academy of Sciences of the USA 74: 5463–5467.

    Article  CAS  Google Scholar 

  163. Schinkel, A.H., and J.W. Jonker. 2003. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Advanced Drug Delivery Reviews 55: 3–29.

    Article  CAS  PubMed  Google Scholar 

  164. Schroder, S., K. Beckmann, G. Franconi, G. Meyer-Hamme, T. Friedemann, H.J. Greten, M. Rostock, and T. Efferth. 2013. Can medical herbs stimulate regeneration or neuroprotection and treat neuropathic pain in chemotherapy-induced peripheral neuropathy? Evidence-based Complementary and Alternative Medicine 2013: 423713.

    PubMed  PubMed Central  Google Scholar 

  165. Seca, A.M.L., and D.C.G.A. Pinto. 2018. Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application. International Journal of Molecular Sciences 19: 263.

    Article  PubMed Central  CAS  Google Scholar 

  166. Seigler, D.S. 2012. Plant secondary metabolism. New York: Springer.

    Google Scholar 

  167. Seo, E.J., B. Wiench, R. Hamm, M. Paulsen, Y. Zu, Y. Fu, and T. Efferth. 2015. Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres. Phytomedicine 22: 438–443.

    Article  CAS  PubMed  Google Scholar 

  168. Seo, E.-J., M. Saeed, B.Y.K. Law, A.G. Wu, O. Kadioglu, H.J. Greten, and T. Efferth. 2016. Pharmacogenomics of scopoletin in tumor cells. Molecules 21: 496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Seo, E.-J., S.M. Klauck, T. Efferth, and A. Panossian. 2019a. Adaptogens in chemobrain (Part I): Plant extracts attenuate cancer chemotherapy-induced cognitive impairment – Transcriptome-wide microarray profiles of neuroglia cells. Phytomedicine 55: 80–91.

    Article  CAS  PubMed  Google Scholar 

  170. ———. 2019b. Adaptogens in chemobrain (Part III): Antitoxic effects of plant extracts towards cancer chemotherapy-induced toxicity – transcriptome-wide microarray analysis of neuroglia cells. Phytomedicine 56: 246–260.

    Article  CAS  PubMed  Google Scholar 

  171. Siveen, K.S., S. Sikka, R. Surana, X. Dai, J. Zhang, A.P. Kumar, B.K.H. Tan, G. Sethi, and A. Bishayee. 2014. Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer 1845: 136–154.

    Article  CAS  Google Scholar 

  172. Song, X., Y. Xiong, X. Qi, W. Tang, J. Dai, Q. Gu, and J. Li. 2018. Molecular targets of active anticancer compounds derived from marine sources. Marine Drugs 16: 175.

    Article  PubMed Central  CAS  Google Scholar 

  173. Stähblin, H. 1973. Activity of a new glycosidic lignan derivative (VP 16-213) related to podophyllotoxin in experimental tumors. European Journal of Cancer (1965) 9: 215–221.

    Article  Google Scholar 

  174. Sun, Y., W. Zhang, Y. Chen, Q. Ma, J. Wei, and Q. Liu. 2016. Identifying anti-cancer drug response related genes using an integrative analysis of transcriptomic and genomic variations with cell line-based drug perturbations. Oncotarget 7: 9404–9419.

    PubMed  PubMed Central  Google Scholar 

  175. Szakacs, G., J.K. Paterson, J.A. Ludwig, C. Booth-Genthe, and M.M. Gottesman. 2006. Targeting multidrug resistance in cancer. Nature Reviews. Drug Discovery 5: 219–234.

    Article  CAS  PubMed  Google Scholar 

  176. Tariq, A., S. Sadia, K. Pan, I. Ullah, S. Mussarat, F. Sun, O.O. Abiodun, A. Batbaatar, Z. Li, D. Song, Q. Xiong, R. Ullah, S. Khan, B.B. Basnet, B. Kumar, R. Islam, and M. Adnan. 2017. A systematic review on ethnomedicines of anti-cancer plants. Phytotherapy Research 31: 202–264.

    Article  PubMed  Google Scholar 

  177. TM-MC: A database of medicinal materials and chemical compounds in Northeast Asian traditional medicine 2018, Introduction, viewed 10.02.2019. http://informatics.kiom.re.kr/compound/

  178. Trudeau, R.J. 2013. Introduction to graph theory. New York: Dover Publications.

    Google Scholar 

  179. Turkson, J., and R. Jove. 2000. STAT proteins: Novel molecular targets for cancer drug discovery. Oncogene 19: 6613–6626.

    Article  CAS  PubMed  Google Scholar 

  180. Tyanova, S., and J. Cox. 2018. Perseus: A bioinformatics platform for integrative analysis of proteomics data in cancer research. In Cancer systems biology: Methods and protocols, ed. L. Von Stechow. New York: Humana Press.

    Google Scholar 

  181. Uzuner, H., R. Bauer, T.-P. Fan, D.-A. Guo, A. Dias, H. El-Nezami, T. Efferth, E.M. Williamson, M. Heinrich, N. Robinson, P.J. Hylands, B.M. Hendry, Y.-C. Cheng, and Q. Xu. 2012. Traditional Chinese medicine research in the post-genomic era: Good practice, priorities, challenges and opportunities. Journal of Ethnopharmacology 140: 458–468.

    Article  PubMed  Google Scholar 

  182. Valouev, A., D.S. Johnson, A. Sundquist, C. Medina, E. Anton, S. Batzoglou, R.M. Myers, and A. Sidow. 2008. Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nature Methods 5: 829–834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Verdine, G.L. 1996. The combinatorial chemistry of nature. Nature 384: 11–13.

    Article  CAS  PubMed  Google Scholar 

  184. Vilgis, S., and H.-P. Deigner. 2018. Sequencing in precision medicine. In Precision medicine, ed. H.-P. Deigner and M. Kohl. London: Academic Press.

    Google Scholar 

  185. Vogel, H.G. 1991. Similarities between various systems of traditional medicine. Considerations for the future of ethnopharmacology. Journal of Ethnopharmacology 35: 179–190.

    Article  CAS  PubMed  Google Scholar 

  186. ———. 2002. Drug discovery and evaluation: Pharmacological assays. Heidelberg: Springer. Viewed 8 February 2019. https://www.springer.com/gp/book/9783540709954

  187. Volm, M., and T. Efferth. 2015. Prediction of cancer drug resistance and implications for personalized medicine. Frontiers in Oncology 5: 282.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Walther, Z., and J. Sklar. 2011. Molecular tumor profiling for prediction of response to anticancer therapies. Cancer Journal 17: 71–79.

    Article  CAS  PubMed  Google Scholar 

  189. Wang, M., R.J. Lamers, H.A. Korthout, J.H. Van Nesselrooij, R.F. Witkamp, R. Van Der Heijden, P.J. Voshol, L.M. Havekes, R. Verpoorte, and J. Van Der Greef. 2005. Metabolomics in the context of systems biology: Bridging traditional Chinese medicine and molecular pharmacology. Phytotherapy Research 19: 173–182.

    Article  CAS  PubMed  Google Scholar 

  190. Wang, Y., X. Wang, and Y. Cheng. 2006. A computational approach to botanical drug design by modeling quantitative composition–activity relationship. Chemical Biology & Drug Design 68: 166–172.

    Article  CAS  Google Scholar 

  191. Wang, H., F. Lafdil, X. Kong, and B. Gao. 2011. Signal transducer and activator of transcription 3 in liver diseases: A novel therapeutic target. International Journal of Biological Sciences 7: 536–550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wang, R.-S., A. Saadatpour, and R. Albert. 2012. Boolean modeling in systems biology: An overview of methodology and applications. Physical Biology 9: 055001.

    Article  PubMed  CAS  Google Scholar 

  193. Wang, J., Y. Li, Y. Yang, J. Du, M. Zhao, F. Lin, S. Zhang, and B. Wang. 2017. Systems pharmacology dissection of multiscale mechanisms of action for herbal medicines in treating rheumatoid arthritis. Molecular Pharmacology 14: 3201–3217.

    Article  CAS  Google Scholar 

  194. Wang, C., P. Xu, L. Zhang, J. Huang, K. Zhu, and C. Luo. 2018. Current strategies and applications for precision drug design. Frontiers in Pharmacology 9: 787–787.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Weerasinghe, P., Y. Li, Y. Guan, R. Zhang, D.J. Tweardy, and N. Jing. 2008. T40214/PEI complex: A potent therapeutics for prostate cancer that targets STAT3 signaling. Prostate 68: 1430–1442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Wen, Z., Z. Wang, S. Wang, R. Ravula, L. Yang, J. Xu, C. Wang, Z. Zuo, M.S. Chow, L. Shi, and Y. Huang. 2011. Discovery of molecular mechanisms of traditional Chinese medicinal formula Si-Wu-Tang using gene expression microarray and connectivity map. PLoS One 6: e18278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Willett, P., J.M. Barnard, and G.M. Downs. 1998. Chemical similarity searching. Journal of Chemical Information and Computer Sciences 38: 983–996.

    Article  CAS  Google Scholar 

  198. Williams, S.D., R. Birch, L.H. Einhorn, L. Irwin, F.A. Greco, and P.J. Loehrer. 1987. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. The New England Journal of Medicine 316: 1435–1440.

    Article  CAS  PubMed  Google Scholar 

  199. Wong, A.M., Y. Zhang, K. Kesler, M. Deng, L. Burhenn, D. Wang, A. Moro, Z. Li, and D. Heber. 2010. Genomic and in vivo evidence of synergy of a herbal extract compared to its most active ingredient: Rabdosia rubescens vs. oridonin. Experimental and Therapeutic Medicine 1: 1013–1017.

    Article  PubMed  PubMed Central  Google Scholar 

  200. World Health Organization. 2019. Cancer, viewed 4 February 2019. https://www.who.int/cancer/en/

  201. Wu, J., and R. Ji. 1989. Application of QSAR in drug design. Foreign Med Sci·Pharm Sect (Chin) 16: 8–16.

    Google Scholar 

  202. Wu, D., C.M. Rice, and X. Wang. 2012. Cancer bioinformatics: A new approach to systems clinical medicine. BMC Bioinformatics 13: 71.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Wu, Q., Z. Yang, Y. Nie, Y. Shi, and D. Fan. 2014. Multi-drug resistance in cancer chemotherapeutics: Mechanisms and lab approaches. Cancer Letters 347: 159–166.

    Article  CAS  PubMed  Google Scholar 

  204. Wu, C.F., C. Hong, S.M. Klauck, Y.L. Lin, and T. Efferth. 2015. Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells. Journal of Ethnopharmacology 176: 55–68.

    Article  CAS  PubMed  Google Scholar 

  205. Yang, J., X. Liao, M.K. Agarwal, L. Barnes, P.E. Auron, and G.R. Stark. 2007. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes & Development 21: 1396–1408.

    Article  CAS  Google Scholar 

  206. Yang, H.J., D. Shen, H.-Y. Xu, and P. Lu. 2012. A new strategy in drug design of Chinese medicine: Theory, method and techniques. Chinese Journal of Integrative Medicine 18: 803–806.

    Article  CAS  PubMed  Google Scholar 

  207. Youns, M., Y.J. Fu, Y.G. Zu, A. Kramer, V.B. Konkimalla, B. Radlwimmer, H. Sultmann, and T. Efferth. 2010. Sensitivity and resistance towards isoliquiritigenin, doxorubicin and methotrexate in T cell acute lymphoblastic leukaemia cell lines by pharmacogenomics. Naunyn-Schmiedeberg’s Archives of Pharmacology 382: 221–234.

    Article  CAS  PubMed  Google Scholar 

  208. Yu, H., D. Pardoll, and R. Jove. 2009. STATs in cancer inflammation and immunity: A leading role for STAT3. Nature Reviews Cancer 9: 798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Yue, Z., W. Zhang, Y. Lu, Q. Yang, Q. Ding, J. Xia, and Y. Chen. 2015. Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties. PeerJ- the Journal of Life and Environmental Sciences 3: e1425–e1425.

    Google Scholar 

  210. Zhang, P., and V. Brusic. 2014. Mathematical modeling for novel cancer drug discovery and development. Expert Opinion on Drug Discovery 9: 1133–1150.

    Article  CAS  PubMed  Google Scholar 

  211. Zhang, H.-F., and R. Lai. 2014. STAT3 in cancer-friend or foe? Cancers 6: 215–1440.

    Article  CAS  Google Scholar 

  212. Zhang, S., W. Lu, X. Liu, Y. Diao, F. Bai, L. Wang, L. Shan, J. Huang, H. Li, and W. Zhang. 2011. Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach. Medicinal Chemistry Communications 2: 471–477.

    Article  CAS  Google Scholar 

  213. Zhang, A., H. Sun, P. Wang, Y. Han, and X. Wang. 2012. Future perspectives of personalized medicine in traditional Chinese medicine: A systems biology approach. Complementary Therapies in Medicine 20: 93–99.

    Article  PubMed  Google Scholar 

  214. Zhao, J., P. Jiang, and W. Zhang. 2010. Molecular networks for the study of TCM pharmacology. Briefings in Bioinformatics 11: 417–430.

    Article  CAS  PubMed  Google Scholar 

  215. Zheng, H.C., A. Noguchi, K. Kikuchi, T. Ando, T. Nakamura, and Y. Takano. 2014. Gene expression profiling of lens tumors, liver and spleen in alpha-crystallin/SV40 T antigen transgenic mice treated with Juzen-taiho-to. Molecular Medicine Reports 9: 547–552.

    Article  CAS  PubMed  Google Scholar 

  216. Zhou, X., Y. Peng, and B. Liu. 2010. Text mining for traditional Chinese medical knowledge discovery: A survey. Journal of Biomedical Informatics 43: 650–660.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey

    Nadire Özenver

  2. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany

    Thomas Efferth

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    Mariano Bizzarri

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Özenver, N., Efferth, T. (2020). Integration of Phytochemicals and Phytotherapy into Cancer Precision Medicine. In: Bizzarri, M. (eds) Approaching Complex Diseases. Human Perspectives in Health Sciences and Technology, vol 2. Springer, Cham. https://doi.org/10.1007/978-3-030-32857-3_16

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