The anticancer properties of Herba Epimedii and its main bioactive componentsicariin and icariside II

Nutrients

Volumn 8, Issue 9, 2016, Pages

  Chen, Meixia ^a   Wu, Jinfeng ^a   Luo, Qingli ^a   Mo, Shuming ^a   Lyu, Yubao ^a   Wei, Ying ^a   Dong, Jingcheng ^a  

^a FUDAN UNIVERSITY   (China)

Author keywords

Anticancer properties; Herba Epimedii; Icariin; Icariside II

Indexed keywords

APOPTOSIS INDUCING FACTOR; APOPTOTIC PROTEASE ACTIVATING FACTOR 1; ARSENIC TRIOXIDE; BORTEZOMIB; CYCLIN A; CYCLIN B1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; CYTOCHROME C; DOXORUBICIN; FLAVONOID; FLUOROURACIL; GEMCITABINE; HERBA EPIMEDII EXTRACT; ICARIIN; ICARISIDE II; JANUS KINASE 2; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PLANT EXTRACT; PROTEIN KINASE B; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; TEMOZOLOMIDE; THALIDOMIDE; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; BAOHUOSIDE I; EPIMEDII FLAVONE; HERBACEOUS AGENT;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BONE DENSITY; CANCER ADJUVANT THERAPY; CANCER CELL LINE; CELL CYCLE REGULATION; DRUG CYTOTOXICITY; HERBA EPIMEDII; HUMAN; IC50; INTRACELLULAR SIGNALING; MEDICINAL PLANT; METASTASIS; NONHUMAN; PHYTOCHEMISTRY; REVIEW; TUMOR VOLUME; CHEMISTRY; NEOPLASMS; PHYTOTHERAPY;

DRUGS, CHINESE HERBAL; FLAVONOIDS; HUMANS; NEOPLASMS; PHYTOTHERAPY;

EID: 84987735529     PISSN: None     EISSN: 20726643     Source Type: Journal    
DOI: 10.3390/nu8090563     Document Type: Review

References (103)

1. Siegel, R.L., Miller, K.D., Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 2016, 66, 7–30. [CrossRef] [PubMed]
2. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015, 136, E359–E386. [CrossRef] [PubMed]
3. Graham, J.G., Quinn, M.L., Fabricant, D.S., Farnsworth, N.R. Plants used against cancer-an extension of Jonathan Hartwell. J. Ethnopharmacol. 2000, 73, 347–377. [CrossRef]
4. Amin, A.R., Kucuk, O., Khuri, F.R., Shin, D.M. Perspectives for cancer prevention with natural compounds. J. Clin. Oncol. 2009, 27, 2712–2725. [CrossRef] [PubMed]
5. Zhang, X., Chen, L.X., Ouyang, L., Cheng, Y., Liu, B. Plant natural compounds: Targeting pathways of autophagy as anti-cancer therapeutic agents. Cell Prolif. 2012, 45, 466–476. [CrossRef] [PubMed]
6. Cragg, G.M., Newman, D.J. Plants as a source of anti-cancer agents. J. Ethnopharmacol. 2005, 100, 72–79. [CrossRef] [PubMed]
7. Kumar, A., Patil, D., Rajamohanan, P.R., Ahmad, A. Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus. PLoS ONE 2013, 8, e71805. [CrossRef] [PubMed]
8. Nemeth, L., Somfai, S., Gal, F., Kellner, B. Comparative studies concerning the tumour inhibition and the toxicology of vinblastine and vincristine. Neoplasma 1970, 17, 345–347. [PubMed]
9. Cipriani, D. Clinical experience with vinblastine and vincristine. Cancro 1968, 21, 185–189. [PubMed]
10. Editorial Committee of China Pharmacopoeia. The Chinese Pharmacopoeia, Part I, 2015 ed., China Chemical Industry Press: Beijing, China, 2015, p. 486.
11. Ma, H., He, X., Yang, Y., Li, M., Hao, D., Jia, Z. The genus Epimedium: An ethnopharmacological and phytochemical review. J. Ethnopharmacol. 2011, 134, 519–541. [CrossRef] [PubMed]
12. Xie, F., Wu, C.F., Lai, W.P., Yang, X.J., Cheung, P.Y., Yao, X.S., Leung, P.C., Wong, M.S. The osteoprotective effect of Herba epimedii (HEP) extract in vivo and in vitro. Evid. Based Complement. Altern. Med. 2005, 2, 353–361. [CrossRef] [PubMed]
13. Wang, L., Li, Y., Guo, Y., Ma, R., Fu, M., Niu, J., Gao, S., Zhang, D. Herba Epimedii: An Ancient Chinese Herbal Medicine in the Prevention and Treatment of Osteoporosis. Curr. Pharm. Des. 2016, 22, 328–349. [CrossRef] [PubMed]
14. Niu, R.: Action of the drug Herba Epimedii on testosterone of the mouse plasma and its accessory sexual organ before and after processing. China J. Chin. Mater. Med. 1989, 14, 530–574.
15. Yu, L., Li, H., Huang, G., Bai, Y., Dong, Y. Clinical observations on treatment of 120 cases of coronary heart disease with herba epimedii. J. Tradit. Chin. Med. 1992, 12, 30–34. [PubMed]
16. Zhao, Y.L., Song, H.R., Fei, J.X., Liang, Y., Zhang, B.H., Liu, Q.P., Wang, J., Hu, P. The effects of Chinese yam-epimedium mixture on respiratory function and quality of life in patients with chronic obstructive pulmonary disease. J. Tradit. Chin. Med. 2012, 32, 203–207. [CrossRef]
17. Lin, C.C., Ng, L.T., Hsu, F.F., Shieh, D.E., Chiang, L.C. Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin. Exp. Pharmacol. Physiol. 2004, 31, 65–69. [CrossRef] [PubMed]
18. Khan, M., Maryam, A., Qazi, J.I., Ma, T.: Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells. Int. J. Biol. Sci. 2015, 11, 1100–1112. [CrossRef] [PubMed]
19. Huang, H., Liang, M., Zhang, X., Zhang, C., Shen, Z., Zhang, W.: Simultaneous determination of nine flavonoids and qualitative evaluation of Herba Epimedii by high performance liquid chromatography with ultraviolet detection. J. Sep. Sci. 2007, 30, 3207–3213. [CrossRef] [PubMed]
20. Pei, L.K., Guo, B.L.: A review on research of raw material and cut crude drug of Herba epimedii in last ten years. China J. Chin. Mater. Med. 2007, 32, 466–471.
21. Xie, X., Pei, F., Wang, H., Tan, Z., Yang, Z., Kang, P. Icariin: A promising osteoinductive compound for repairing bone defect and osteonecrosis. J. Biomater. Appl. 2015, 30, 290–299. [CrossRef] [PubMed]
22. Wei, Y., Liu, B., Sun, J., Lv, Y., Luo, Q., Liu, F., Dong, J. Regulation of Th17/Treg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model. Immunobiology 2015, 220, 789–797. [CrossRef] [PubMed]
23. Chen, S.R., Xu, X.Z., Wang, Y.H., Chen, J.W., Xu, S.W., Gu, L.Q., Liu, P.Q.: Icariin derivative inhibits inflammation through suppression of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. Biol. Pharm. Bull. 2010, 33, 1307–1313. [CrossRef] [PubMed]
24. Xiong, W., Chen, Y., Wang, Y., Liu, J.: Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis. BMC Vet. Res. 2014, 10. [CrossRef] [PubMed]
25. Lee, M.K., Choi, Y.J., Sung, S.H., Shin, D.I., Kim, J.W., Kim, Y.C. Antihepatotoxic activity of icariin, a major constituent of Epimedium koreanum. Planta Med. 1995, 61, 523–526. [CrossRef] [PubMed]
26. Liu, B., Xu, C., Wu, X., Liu, F., Du, Y., Sun, J., Tao, J., Dong, J. Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation. Neuroscience 2015, 294, 193–205. [CrossRef] [PubMed]
27. Liu, B., Zhang, H., Xu, C., Yang, G., Tao, J., Huang, J., Wu, J., Duan, X., Cao, Y., Dong, J. Neuroprotective effects of icariin on corticosterone-induced apoptosis in primary cultured rat hippocampal neurons. Brain Res. 2011, 1375, 59–67. [CrossRef] [PubMed]
28. Meng, X., Pei, H., Lan, C. Icariin Exerts Protective Effect Against Myocardial Ischemia/Reperfusion Injury in Rats. Cell Biochem. Biophys. 2015, 73, 229–235. [CrossRef] [PubMed]
29. Zhai, M., He, L., Ju, X., Shao, L., Li, G., Zhang, Y., Liu, Y., Zhao, H. Icariin Acts as a Potential Agent for Preventing Cardiac Ischemia/Reperfusion Injury. Cell Biochem. Biophys. 2015, 72, 589–597. [CrossRef] [PubMed]
30. Hu, Y., Liu, K., Yan, M., Zhang, Y., Wang, Y., Ren, L.: Effects and mechanisms of icariin on atherosclerosis. Int. J. Clin. Exp. Med. 2015, 8, 3585–3589. [PubMed]
31. Xia, Q., Xu, D., Huang, Z., Liu, J., Wang, X., Wang, X., Liu, S. Preparation of icariside II from icariin by enzymatic hydrolysis method. Fitoterapia 2010, 81, 437–442. [CrossRef] [PubMed]
32. Luo, G., Gu, F., Zhang, Y., Liu, T., Guo, P., Huang, Y. Icariside II promotes osteogenic differentiation of bone marrow stromal cells in beagle canine. Int. J. Clin. Exp. Pathol. 2015, 8, 4367–4377. [PubMed]
33. Yin, C., Deng, Y., Gao, J., Li, X., Liu, Y., Gong, Q. Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats. Neuroscience 2016, 328, 69–79. [CrossRef] [PubMed]
34. Deng, Y., Xiong, D., Yin, C., Liu, B., Shi, J., Gong, Q. Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor up-regulation. Neurochem. Int. 2016, 96, 56–61. [CrossRef] [PubMed]
35. Chen, X., Tang, L., Li, Q. Antiproliferative activities of alcohol extracts of Herba Epimedii and Cortex Fraxini on breast cancer cell proliferation: In vitro study. China Pharm. 2007, 18, 1124–1127.
36. Yao, X., Jia, L.Q., Tan, H.Y., Gao, F.Y., Cui, J., Li, H.: Effects of Epimedium on rat tumor growth and bone destruction of breast cancer rats with bone metastasis. Beijing J. Trad. Chin. Med. 2008, 27, 882–884.
37. Wang, Z.M., Song, N., Ren, Y.L.: Anti-proliferative and cytoskeleton-disruptive effects of icariin on HepG2 cells. Mol. Med. Rep. 2015, 12, 6815–6820. [CrossRef] [PubMed]
38. Li, S., Dong, P., Wang, J., Zhang, J., Gu, J., Wu, X., Wu, W., Fei, X., Zhang, Z., Wang, Y. et al. Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway. Cancer Lett. 2010, 298, 222–230. [CrossRef] [PubMed]
39. Huang, X., Zhu, D., Lou, Y.: A novel anticancer agent, icaritin, induced cell growth inhibition, G1 arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells. Eur. J. Pharmacol. 2007, 564, 26–36. [CrossRef] [PubMed]
40. Lee, K.S., Lee, H.J., Ahn, K.S., Kim, S.H., Nam, D., Kim, D.K., Choi, D.Y., Ahn, K.S., Lu, J., Kim, S.H. Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells. Cancer Lett. 2009, 280, 93–100. [CrossRef] [PubMed]
41. Fan, C., Yang, Y., Liu, Y., Jiang, S., Di, S., Hu, W., Ma, Z., Li, T., Zhu, Y., Xin, Z. et al. Icariin displays anticancer activity against human esophageal cancer cells via regulating endoplasmic reticulum stress-mediated apoptotic signaling. Sci. Rep. 2016, 6. [CrossRef] [PubMed]
42. Li, J., Jiang, K., Zhao, F. Icariin regulates the proliferation and apoptosis of human ovarian cancer cells through microRNA-21 by targeting PTEN, RECK and Bcl-2. Oncol. Rep. 2015, 33, 2829–2836. [CrossRef] [PubMed]
43. Di, S., Fan, C., Yang, Y., Jiang, S., Liang, M., Wu, G., Wang, B., Xin, Z., Hu, W., Zhu, Y. et al. Activation of endoplasmic reticulum stress is involved in the activity of icariin against human lung adenocarcinoma cells. Apoptosis 2015, 20, 1229–1241. [CrossRef] [PubMed]
44. Song, J., Feng, L., Zhong, R., Xia, Z., Zhang, L., Cui, L., Yan, H., Jia, X., Zhang, Z. Icariside II inhibits the EMT of NSCLC cells in inflammatory microenvironment via down-regulation of Akt/NF-kappaB signaling pathway. Mol. Carcinog. 2016. [CrossRef] [PubMed]
45. Li, X., Sun, J., Hu, S., Liu, J. Icariin Induced B16 Melanoma Tumor Cells Apoptosis, Suppressed Tumor Growth and Metastasis. Iran. J. Public Health 2014, 43, 847–848. [PubMed]
46. Wu, J., Song, T., Liu, S., Li, X., Li, G., Xu, J.: Icariside II inhibits cell proliferation and induces cell cycle arrest through the ROS-p38-p53 signaling pathway in A375 human melanoma cells. Mol. Med. Rep. 2015, 11, 410–416. [CrossRef] [PubMed]
47. Wu, J., Xu, J., Eksioglu, E.A., Chen, X., Zhou, J., Fortenbery, N., Wei, S., Dong, J. Icariside II induces apoptosis of melanoma cells through the downregulation of survival pathways. Nutr. Cancer 2013, 65, 110–117. [CrossRef] [PubMed]
48. Wu, J., Guan, M., Wong, P.F., Yu, H., Dong, J., Xu, J. Icariside II potentiates paclitaxel-induced apoptosis in human melanoma A375 cells by inhibiting TLR4 signaling pathway. Food Chem. Toxicol. 2012, 50, 3019–3024. [CrossRef] [PubMed]
49. Wang, Q., Hao, J., Pu, J., Zhao, L., Lu, Z., Hu, J., Yu, Q., Wang, Y., Xie, Y., Li, G.: Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil 4. Int. J. Oncol. 2011, 39, 973–980. [PubMed]
50. Wang, Y., Dong, H., Zhu, M., Ou, Y., Zhang, J., Luo, H., Luo, R., Wu, J., Mao, M., Liu, X. et al. Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. Eur. J. Pharmacol. 2010, 635, 40–48. [CrossRef] [PubMed]
51. Sun, Y., Sun, X.H., Fan, W.J., Jiang, X.M., Li, A.W.: Icariin induces S-phase arrest and apoptosis in medulloblastoma cells. Cell Mol. Biol. 2016, 62, 123–129. [PubMed]
52. Zhang, C., Yang, L., Geng, Y.D., An, F.L., Xia, Y.Z., Guo, C., Luo, J.G., Zhang, L.Y., Guo, Q.L., Kong, L.Y. Icariside II, a natural mTOR inhibitor, disrupts aberrant energy homeostasis via suppressing mTORC1–4E-BP1 axis in sarcoma cells. Oncotarget 2016. [CrossRef] [PubMed]
53. Geng, Y.D., Zhang, C., Shi, Y.M., Xia, Y.Z., Guo, C., Yang, L., Kong, L.Y. Icariside II-induced mitochondrion and lysosome mediated apoptosis is counterbalanced by an autophagic salvage response in hepatoblastoma. Cancer Lett. 2015, 366, 19–31. [CrossRef] [PubMed]
54. Geng, Y.D., Yang, L., Zhang, C., Kong, L.Y. Blockade of epidermal growth factor receptor/mammalian target of rapamycin pathway by Icariside II results in reduced cell proliferation of osteosarcoma cells. Food Chem. Toxicol. 2014, 73, 7–16. [CrossRef] [PubMed]
55. Choi, H.J., Eun, J.S., Kim, D.K., Li, R.H., Shin, T.Y., Park, H., Cho, N.P., Soh, Y. Icariside II from Epimedium koreanum inhibits hypoxia-inducible factor-1alpha in human osteosarcoma cells. Eur. J. Pharmacol. 2008, 579, 58–65. [CrossRef] [PubMed]
56. Wu, J., Zuo, F., Du, J., Wong, P.F., Qin, H., Xu, J. Icariside II induces apoptosis via inhibition of the EGFR pathways in A431 human epidermoid carcinoma cells. Mol. Med. Rep. 2013, 8, 597–602. [PubMed]
57. Kang, S.H., Jeong, S.J., Kim, S.H., Kim, J.H., Jung, J.H., Koh, W., Kim, J.H., Kim, D.K., Chen, C.Y., Kim, S.H. Icariside II induces apoptosis in U937 acute myeloid leukemia cells: Role of inactivation of STAT3-related signaling. PLoS ONE 2012, 7, e28706. [CrossRef] [PubMed]
58. Huang, C., Chen, X., Guo, B., Huang, W., Shen, T., Sun, X., Xiao, P., Zhou, Q.: Induction of apoptosis by Icariside II through extrinsic and intrinsic signaling pathways in human breast cancer MCF7 cells. Biosci. Biotechnol. Biochem. 2012, 76, 1322–1328. [CrossRef] [PubMed]
59. Kim, S.H., Ahn, K.S., Jeong, S.J., Kwon, T.R., Jung, J.H., Yun, S.M., Han, I., Lee, S.G., Kim, D.K., Kang, M. et al. Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells. Eur. J. Pharmacol. 2011, 654, 10–16. [CrossRef] [PubMed]
60. Zhou, J., Wu, J., Chen, X., Fortenbery, N., Eksioglu, E., Kodumudi, K.N., Pk, E.B., Dong, J., Djeu, J.Y., Wei, S. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int. Immunopharmacol. 2011, 11, 890–898. [CrossRef] [PubMed]
61. Yang, J.X., Fichtner, I., Becker, M., Lemm, M., Wang, X.M.: Anti-proliferative efficacy of icariin on HepG2 hepatoma and its possible mechanism of action. Am. J. Chin. Med. 2009, 37, 1153–1165. [CrossRef] [PubMed]
62. Yang, L., Wang, Y., Guo, H., Guo, M. Synergistic Anti-Cancer Effects of Icariin and Temozolomide in Glioblastoma. Cell Biochem. Biophys. 2015, 71, 1379–1385. [CrossRef] [PubMed]
63. Wang, Z., Zhang, H., Dai, L., Song, T., Li, P., Liu, Y., Wang, L.: Arsenic Trioxide and Icariin Show Synergistic Anti-leukemic Activity. Cell Biochem. Biophys. 2015, 73, 213–219. [CrossRef] [PubMed]
64. Li, W., Wang, M., Wang, L., Ji, S., Zhang, J., Zhang, C. Icariin synergizes with arsenic trioxide to suppress human hepatocellular carcinoma. Cell Biochem. Biophys. 2014, 68, 427–436. [CrossRef] [PubMed]
65. Wang, Z., Yang, L., Xia, Y., Guo, C., Kong, L.: Icariin enhances cytotoxicity of doxorubicin in human multidrug-resistant osteosarcoma cells by inhibition of ABCB1 and down-regulation of the PI3K/Akt pathway. Biol. Pharm. Bull. 2015, 38, 277–284. [CrossRef] [PubMed]
66. Shi, D.B., Li, X.X., Zheng, H.T., Li, D.W., Cai, G.X., Peng, J.J., Gu, W.L., Guan, Z.Q., Xu, Y., Cai, S.J.: Icariin-mediated inhibition of NF-kappaB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer. Cell Biochem. Biophys. 2014, 69, 523–530. [CrossRef] [PubMed]
67. Zhang, D.C., Liu, J.L., Ding, Y.B., Xia, J.G., Chen, G.Y. Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-kappaB. Acta Pharmacol. Sin. 2013, 34, 301–308. [CrossRef] [PubMed]
68. Kelly, M.G., Alvero, A.B., Chen, R., Silasi, D.A., Abrahams, V.M., Chan, S., Visintin, I., Rutherford, T., Mor, G. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006, 66, 3859–3868. [CrossRef] [PubMed]
69. Nurse, P., Masui, Y., Hartwell, L. Understanding the cell cycle. Nat. Med. 1998, 4, 1103–1106. [CrossRef] [PubMed]
70. Sa, G., Das, T. Anti cancer effects of curcumin: Cycle of life and death. Cell Div. 2008, 3, 14. [CrossRef] [PubMed]
71. Elledge, S.J. Cell cycle checkpoints: Preventing an identity crisis. Science 1996, 274, 1664–1672. [CrossRef] [PubMed]
72. Leonard, C.J., Canman, C.E., Kastan, M.B. The role of p53 in cell-cycle control and apoptosis: Implications for cancer. Important Adv. Oncol. 1995, 121, 33–42.
73. Kastan, M.B., Canman, C.E., Leonard, C.J.: P53, cell cycle control and apoptosis: Implications for cancer. Cancer Metastasis Rev. 1995, 14, 3–15. [CrossRef] [PubMed]
74. Bulavin, D.V., Saito, S., Hollander, M.C., Sakaguchi, K., Anderson, C.W., Appella, E., Fornace, A.J., Jr.. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 1999, 18, 6845–6854. [CrossRef] [PubMed]
75. Vermeulen, K., Van Bockstaele, D.R., Berneman, Z.N. The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003, 36, 131–149. [CrossRef] [PubMed]
76. Hall, M., Peters, G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. 1996, 68, 67–108. [PubMed]
77. Noble, M., Barrett, P., Endicott, J., Johnson, L., McDonnell, J., Robertson, G., Zawaira, A. Exploiting structural principles to design cyclin-dependent kinase inhibitors. Biochim. Biophys. Acta 2005, 1754, 58–64. [CrossRef] [PubMed]
78. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [CrossRef] [PubMed]
79. Cotter, T.G. Apoptosis and cancer: The genesis of a research field. Nat. Rev. Cancer 2009, 9, 501–507. [CrossRef] [PubMed]
80. Ashkenazi, A., Dixit, V.M. Death receptors: Signaling and modulation. Science 1998, 281, 1305–1308. [CrossRef] [PubMed]
81. Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H., Peter, M.E. Cytotoxicity-Dependent Apo-1 (Fas/Cd95)-Associated Proteins Form a Death-Inducing Signaling Complex (Disc) with the Receptor. EMBO. J. 1995, 14, 5579–5588. [PubMed]
82. Saelens, X., Festjens, N., VandeWalle, L., van Gurp, M., van Loo, G., Vandenabeele, P. Toxic proteins released from mitochondria in cell death. Oncogene 2004, 23, 2861–2874. [CrossRef] [PubMed]
83. Chinnaiyan, A.M. The apoptosome: Heart and soul of the cell death machine. Neoplasia. 1999, 1, 5–15. [CrossRef] [PubMed]
84. Cory, S., Adams, J.M. The Bcl2 family: Regulators of the cellular life-or-death switch. Nat. Rev. Cancer. 2002, 2, 647–656. [CrossRef] [PubMed]
85. Schuler, M., Green, D.R. Mechanisms of p53-dependent apoptosis. Biochem. Soc. Trans. 2001, 29, 684–688. [CrossRef] [PubMed]
86. Igney, F.H., Krammer, P.H.: Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer 2002, 2, 277–288. [CrossRef] [PubMed]
87. Aggarwal, B.B. Nuclear factor-kappaB: The enemy within. Cancer Cell 2004, 6, 203–208. [CrossRef] [PubMed]
88. Cao, Y., Liu, Q. Therapeutic targets of multiple angiogenic factors for the treatment of cancer and metastasis. Adv. Cancer Res. 2007, 97, 203–224. [PubMed]
89. Hu, Y., Liu, K., Yan, M., Zhang, Y., Wang, Y., Ren, L.: Icariin inhibits oxidized low-density lipoprotein-induced proliferation of vascular smooth muscle cells by suppressing activation of extracellular signal-regulated kinase 1/2 and expression of proliferating cell nuclear antigen. Mol. Med. Rep. 2016, 13, 2899–2903. [PubMed]
90. Ekstrand, A.J., Sugawa, N., James, C.D., Collins, V.P.: Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc. Natl. Acad. Sci. USA 1992, 89, 4309–4313. [CrossRef] [PubMed]
91. Han, W., Lo, H.W. Landscape of EGFR signaling network in human cancers: Biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012, 318, 124–134. [CrossRef] [PubMed]
92. Mora, L.B., Buettner, R., Seigne, J., Diaz, J., Ahmad, N., Garcia, R., Bowman, T., Falcone, R., Fairclough, R., Cantor, A. et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: Direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002, 62, 6659–6666. [PubMed]
93. Dolled-Filhart, M., Camp, R.L., Kowalski, D.P., Smith, B.L., Rimm, D.L. Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. Clin. Cancer Res. 2003, 9, 594–600. [PubMed]
94. Hsiao, J.R., Jin, Y.T., Tsai, S.T., Shiau, A.L., Wu, C.L., Su, W.C. Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis. Brit. J. Cancer 2003, 89, 344–349. [CrossRef] [PubMed]
95. Santarpia, L., Lippman, S.M., El-Naggar, A.K. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert. Opin. Ther. Targets 2012, 16, 103–119. [CrossRef] [PubMed]
96. Shields, J.M., Pruitt, K., McFall, A., Shaub, A., Der, C.J. Understanding Ras: ‘It ain’t over ‘til it’s over’. Trends Cell Biol. 2000, 10, 147–154. [CrossRef]
97. Liu, P., Cheng, H., Roberts, T.M., Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 2009, 8, 627–644. [CrossRef] [PubMed]
98. Guertin, D.A., Sabatini, D.M. Defining the role of mTOR in cancer. Cancer Cell 2007, 12, 9–22. [CrossRef] [PubMed]
99. Shacter, E., Weitzman, S.A. Chronic inflammation and cancer. Oncology 2002, 16, 217–229. [PubMed]
100. Bunt, S.K., Sinha, P., Clements, V.K., Leips, J., Ostrand-Rosenberg, S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J. Immunol. 2006, 176, 284–290. [CrossRef] [PubMed]
101. Armstrong, L., Davydova, J., Brown, E., Han, J., Yamamoto, M., Vickers, S.M. Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy. Surgery 2012, 152, 114–122. [CrossRef] [PubMed]
102. Ristimaki, A., Honkanen, N., Jankala, H., Sipponen, P., Harkonen, M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997, 57, 1276–1280. [PubMed]
103. Basler, J.W., Piazza, G.A. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective inhibitors for prostate cancer chemoprevention. J. Urol. 2004, 171, S59–S63. [CrossRef] [PubMed]