Natural products targeting autophagy via the PI3k/akt/mTOR pathway as anticancer agents

Anti-Cancer Agents in Medicinal Chemistry

Volumn 13, Issue 7, 2013, Pages 1048-1056

  Sun, Hui ^a,b   Wang, Zhaoye ^c   Yakisich, Juan Sebastian ^d  

^a TONGJI UNIVERSITY SCHOOL OF MEDICINE   (China)

^b TONGJI UNIVERSITY   (China)

^c Zhoushan Hospital of Zhejiang Province   (China)

^d KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Anticancer drugs; Autophagy; Cancer stem cell; Cell death; Natural products; Pi3k akt; Stemness

Indexed keywords

3 INDOLEMETHANOL; ANTINEOPLASTIC AGENT; ANTROQUINONOL; APIGENIN; BETA ELEMENE; CURCUMIN; FENRETINIDE; FISETIN; GAMBOGENIC ACID; GENISTEIN; GERANIOL; MAGNOLOL; MAMMALIAN TARGET OF RAPAMYCIN; MEVINOLIN; MONASCUSPILOIN; MULBERRY EXTRACT; NAPHTHAZARIN; NATURAL PRODUCT; OMEGA 3 FATTY ACID; PHOSPHATIDYLINOSITOL 3 KINASE; PLUMBAGIN; POLYGONATUM CYRTONEMA LECTIN; PROTEIN KINASE B; QUERCETIN; RESVERATROL; ROTTLERIN; SHOGAOL; SILIBININ; TETRAHYDROCURCUMIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOPHAGY; BREAST CANCER; COLON CANCER; DRUG POTENTIATION; GLIOBLASTOMA; GLIOMA; LUNG CANCER; MELANOMA; PROSTATE CANCER; SARCOMA; UTERINE CERVIX CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; AUTOPHAGY; BIOLOGICAL PRODUCTS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84882796035     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/18715206113139990130     Document Type: Article

References (132)

1. Fan, Q. W.; Cheng, C.; Hackett, C.; Feldman, M.; Houseman, B. T.; Nicolaides, T.; Haas-Kogan, D.; James, C. D.; Oakes, S. A.; Debnath, J.; Shokat, K. M., Weiss, W. A. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal., 2010, 3(147), ra81.
2. Wojtkowiak, J.; Rothberg, J. M.; Kumar, V.; Schramm, K. J.; Haller, E.; Proemsey, J. B.; Lloyd, M. C.; Sloane, B. F. Gillies, R. J. Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Res., 2012, 72(16), 3938-3947.
3. Marino, M. L.; Pellegrini, P.; Di Lernia, G.; Djavaheri-Mergny, M.; Brnjic, S.; Zhang, X.; Hagg, M.; Linder, S.; Fais, S.; Codogno, P. De Milito, A. Autophagy is a protective mechanism for human melanoma cells under acidic stress. J. Biol. Chem., 2012, 287(36), 30664-30676.
4. Han, W.; Pan, H.; Chen, Y.; Sun, J.; Wang, Y.; Li, J.; Ge, W.; Feng, L.; Lin, X.; Wang, X.; Wang, X. Jin, H. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One, 2011, 6(6), e18691.
5. Yang, L.; Yu, Y.; Kang, R.; Yang, M.; Xie, M.; Wang, Z.; Tang, D.; Zhao, M.; Liu, L.; Zhang, H. Cao, L. Up-regulated autophagy by endogenous high mobility group box-1 promotes chemoresistance in leukemia cells. Leuk. Lymphoma, 2012, 53(2), 315-322.
6. Boya, P.; González-Polo, R. A.; Casares, N.; Perfettini, J. L.; Dessen, P.; Larochette, N.; Métivier, D.; Meley, D.; Souquere, S.; Yoshimori, T.; Pierron, G.; Codogno, P. Kroemer, G. Inhibition of macroautophagy triggers apoptosis. 2005, 25(3), 1025-1040.
7. Daido, S.; Yamamoto, A.; Fujiwara, K.; Sawaya, R.; Kondo, S. Kondo, Y. Inhibition of the DNA-dependent protein kinase catalytic subunit radiosensitizes malignant glioma cells by inducing autophagy. Cancer Res., 2005, 65(10), 4368-4375.
8. Ito, H.; Daido, S.; Kanzawa, T.; Kondo, S. Kondo, Y. Radiationinduced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int. J. Oncol., 2005, 26(5), 1401-1410.
9. Kanzawa, T.; Germano, I. M.; Komata, T.; Ito, H.; Kondo, Y. Kondo, S. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ., 2004, 11(4), 448-457.
10. Lin, C. J.; Lee, C. C.; Shih, Y. L.; Lin, C. H.; Wang, S. H.; Chen, T. H. Shih, C. M. Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomideinduced apoptosis in glioma cells. PLoS One, 2012, 7(6), e38706.
11. Janku, F.; McConkey, D. J.; Hong, D. S. Kurzrock, R. Autophagy as a target for anticancer therapy. Nat. Rev. Clin. Oncol., 2011, 8(9), 528-539.
12. Chen, S.; Rehman, S. K.; Zhang, W.; Wen, A.; Yao, L. Zhang, J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta, 2010, 1806(2), 220-229.
13. 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(5), 466-476.
14. Ghayad, S. E. Cohen, P. A. Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients. Recent. Pat. Anticancer Drug. Discov., 2010, 5(1), 29-57.
15. Zhao, Y. Sun, Y. Targeting the mTOR-DEPTOR Pathway by CRL E3 Ubiquitin Ligases: Therapeutic Application. Neoplasia, 2012, 14(5), 360-367.
16. Jhanwar-Uniyal, M.; Albert, L.; McKenna, E.; Karsy, M.; Rajdev, P.; Braun, A. Murali, R. Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: role of Akt/mTOR and MAPK pathways. Adv. Enzyme Regul., 2011, 51(1), 164-170.
17. Li, H.; Gao, Q.; Guo, L. Lu, S. H. The PTEN/PI3K/Akt pathway regulates stem-like cells in primary esophageal carcinoma cells. Cancer Biol. Ther., 2011, 11(11), 950-958.
18. Martelli, A. M.; Evangelisti, C.; Follo, M. Y.; Ramazzotti, G.; Fini, M.; Giardino, R.; Manzoli, L.; McCubrey, J. A. Cocco, L. Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cells. Curr. Med. Chem., 2011, 18(18), 2715-2726.
19. Gordy, C. He, Y. W. The crosstalk between autophagy and apoptosis: where does this lead? Protein Cell, 2012, 3(1), 17-27.
20. Shafer, A.; Zhou, C.; Gehrig, P. A.; Boggess, J. F. Bae-Jump, V. L. Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int. J. Cancer., 2010, 126(5), 1144-1154.
21. Chiu, H. W.; Fang, W. H.; Chen, Y. L.; Wu, M. D.; Yuan, G. F.; Ho, S. Y. Wang, Y. J. Monascuspiloin enhances the radiation sensitivity of human prostate cancer cells by stimulating endoplasmic reticulum stress and inducing autophagy. PLoS One, 2012, 7(7), e40462.
22. Din, F. V.; Valanciute, A.; Houde, V. P.; Zibrova, D.; Green, K. A.; Sakamoto, K.; Alessi, D. R. Dunlop, M. G. Aspirin Inhibits mTOR Signaling, Activates AMP-Activated Protein Kinase, and Induces Autophagy in Colorectal Cancer Cells. Gastroenterology, 2012, 142(7), 504-1515. e1513.
23. Uddin, S.; Ahmed, M.; Hussain, A.; Assad, L.; Al-Dayel, F.; Bavi, P.; Al-Kuraya, K. S. Munkarah, A. Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int. J. Cancer., 2010, 126(2), 382-394.
24. Voutsadakis, I. A.; Patrikidou, A.; Tsapakidis, K.; Karagiannaki, A.; Hatzidaki, E.; Stathakis, N. E. Papandreou, C. N. Additive inhibition of colorectal cancer cell lines by aspirin and bortezomib. Int. J. Colorectal Dis., 2010, 25(7), 795-804.
25. Yan, K. H.; Yao, C. J.; Chang, H. Y.; Lai, G. M.; Cheng, A. L. Chuang, S. E. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol. Carcinog., 2010, 49(3), 235-246.
26. Zhao, T. T.; Trinh, D.; Addison, C. L. Dimitroulakos, J. Lovastatin inhibits VEGFR and AKT activation: synergistic cytotoxicity in combination with VEGFR inhibitors. PLoS One, 2010, 5(9), e12563.
27. Misirkic, M.; Janjetovic, K.; Vucicevic, L.; Tovilovic, G.; Ristic, B.; Vilimanovich, U.; Harhaji-Trajkovic, L.; Sumarac-Dumanovic, M.; Micic, D.; Bumbasirevic, V. Trajkovic, V. Inhibition of AMPK-dependent autophagy enhances in vitro antiglioma effect of simvastatin. Pharmacol. Res., 2012, 65(1), 111-119.
28. Sheppard, K.; Kinross, K. M.; Solomon, B.; Pearson, R. B. Phillips, W. A. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit. Rev. Oncog., 2012, 17(1), 69-95.
29. Feng, X.; Lu, B.; Xu, Y.; Li, Q.; Zhou, W.; Yang, Z.; Yang, Z.; Zhao, W.; Shen, Z. Hu, R. Aspirin reduces the apoptotic effect of etoposide via Akt activation and up-regulation of p21(cip). Int. J. Mol. Med., 2011, 28(4), 637-643.
30. Klement, G. L.; Goukassian, D.; Hlatky, L.; Carrozza, J.; Morgan, J. P. Yan, X. Cancer Therapy Targeting the HER2-PI3K Pathway: Potential Impact on the Heart. Front Pharmacol., 2012, 3: 113.
31. Carloni, S.; Girelli, S.; Scopa, C.; Buonocore, G.; Longini, M. Balduini, W. Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy., 2010, 6(3), 366-377.
32. Li-Weber, M. Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Lett., 2010, 332(2), 304-12.
33. Mohan, N.; Banik, N. L. Ray, S. K. Combination of N-(4- hydroxyphenyl) retinamide and apigenin suppressed starvationinduced autophagy and promoted apoptosis in malignant neuroblastoma cells. Neurosci Lett., 2011, 502(1), 24-29.
34. Garcia-Echeverria, C. Blocking the mTOR pathway: a drug discovery perspective. Biochem. Soc. Trans., 2011, 39(2), 451-455.
35. Nakamura, Y.; Yogosawa, S.; Izutani, Y.; Watanabe, H.; Otsuji, E. Sakai, T. A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol. Cancer., 2009, 8, 100.
36. Gossner, G.; Choi, M.; Tan, L.; Fogoros, S.; Griffith, K. A.; Kuenker, M. Liu, J. R. Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells. Gynecol Oncol., 2007, 105(1), 23-30.
37. Kuo, P. L.; Hsu, Y. L. Cho, C. Y. Plumbagin induces G2-M arrest and autophagy by inhibiting the AKT/mammalian target of rapamycin pathway in breast cancer cells. Mol. Cancer Ther., 2006, 5(12), 3209-3221.
38. Kumar, V. B.; Yuan, T. C.; Liou, J. W.; Yang, C. J.; Sung, P. J. Weng, C. F. Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles. Mutat. Res., 2011, 707(1-2), 42-52.
39. Yu, C. C.; Chiang, P. C.; Lu, P. H.; Kuo, M. T.; Wen, W. C.; Chen, P. Guh, J. H. Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells. J. Nutr. Biochem., 2011, 23(8), 900-907.
40. Lu, J. J.; Dang, Y. Y.; Huang, M.; Xu, W. S.; Chen, X. P. Wang, Y. T. Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae - A review. J. Ethnopharmacol., 2012, 143(2), 406-411.
41. Liu, J.; Hu, X. J.; Jin, B.; Qu, X. J.; Hou, K. Z. Liu, Y. P. β- Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells. J Pharm Pharmacol., 2012, 64(1), 146-153.
42. Zhan, Y. H.; Liu, J.; Qu, X. J.; Hou, K. Z.; Wang, K. F.; Liu, Y. P. Wu, B. β-Elemene Induces Apoptosis in Human Renal-cell Carcinoma 786-0 Cells through Inhibition of MAPK/ERK and PI3K/Akt/ mTOR Signalling Pathways. Asian. Pac. J. Cancer Prev., 2012, 13(6), 2739-2744.
43. Saiki, S.; Sasazawa, Y.; Imamichi, Y.; Kawajiri, S.; Fujimaki, T.; Tanida, I.; Kobayashi, H.; Sato, F.; Sato, S.; Ishikawa, K.; Imoto, M. Hattori, N. Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy, 2011, 7(2), 176-187.
44. López-Lázaro, M. Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol. Nutr. Food Res., 2008, 52(Suppl 1), S103-127.
45. Epstein, J.; Sanderson, I. R. Macdonald, T. T. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Br. J. Nutr., 2010, 103(11), 1545-1557.
46. Campbell, F. C. Collett, G. P. Chemopreventive properties of curcumin. Future Oncol., 2005, 1(3), 405-414.
47. Gupta, S. C.; Patchva, S.; Koh, W. Aggarwal, B. B. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin. Exp. Pharmacol. Physiol., 2012, 39(3), 283-299.
48. Aoki, H.; Takada, Y.; Kondo, S.; Sawaya, R.; Aggarwal, B. B. Kondo, Y. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol. Pharmacol., 2007, 72(1), 29-39.
49. Wu, J. C.; Lai, C. S.; Badmaev, V.; Nagabhushanam, K.; Ho, C. T. Pan, M. H. Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells. Mol. Nutr. Food Res., 2011, 55(11), 1646-1654.
50. Adhami, V. M.; Syed, D. N.; Khan, N. Mukhtar, H. Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem. Pharmacol., 2012, 84(10), 1277-81.
51. Khan, N.; Afaq, F.; Khusro, F. H.; Mustafa Adhami, V.; Suh, Y. Mukhtar, H. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int. J. Cancer., 2012, 130(7), 1695-1705.
52. Suh, Y.; Afaq, F.; Khan, N.; Johnson, J. J.; Khusro, F. H. Mukhtar, H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis, 2010, 31(8), 1424-1433.
53. Yang, P. M.; Tseng, H. H.; Peng, C. W.; Chen, W. S. Chiu, S. J. Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int. J. Oncol., 2012, 40(2), 469-478.
54. Li, Q.; Cheng, H.; Zhu, G.; Yang, L.; Zhou, A.; Wang, X.; Fang, N.; Xia, L.; Su, J.; Wang, M.; Peng, D. Xu, Q. Gambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing and cell cycle arresting. Biol Pharm Bull., 2010, 33(3), 415-420.
55. Chen, H. B.; Zhou, L. Z.; Mei, L.; Shi, X. J.; Wang, X. S.; Li, Q. L. Huang, L. Gambogenic acid-induced time- and dose-dependent growth inhibition and apoptosis involving Akt pathway inactivation in U251 glioblastoma cells. J. Nat. Med., 2012, 66(1), 62-69.
56. Yu, X. J.; Han, Q. B.; Wen, Z. S.; Ma, L.; Gao, J. Zhou, G. B. Gambogenic acid induces G1 arrest via GSK3β-dependent cyclin D1 degradation and triggers autophagy in lung cancer cells. Cancer Lett., 2012, 322(2), 185-194.
57. Elson, C. E. Yu, S. G. The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J. Nutr., 1994, 124(5), 607-614.
58. Ong, T. P.; Heidor, R.; de Conti, A.; Dagli, M. L. Moreno, F. S. Farnesol and geraniol chemopreventive activities during the initial phases of hepatocarcinogenesis involve similar actions on cell proliferation and DNA damage, but distinct actions on apoptosis, plasma cholesterol and HMGCoA reductase. Carcinogenesis, 2006, 27(6), 1194-1203.
59. Kim, S. H.; Park, E. J.; Lee, C. R.; Chun, J. N.; Cho, N. H.; Kim, I. G.; Lee, S.; Kim, T. W.; Park, H. H.; So, I., Jeon, J. H. Geraniol induces cooperative interaction of apoptosis and autophagy to elicit cell death in PC-3 prostate cancer cells. Int J Oncol, 2012, 40(5), 1683-1690.
60. Xu, H. L.; Tang, W.; Du, G. H. Kokudo, N. Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinali. Drug. Discov. Ther., 2011, 5(5), 202-210.
61. Li, H. B.; Yi, X.; Gao, J. M.; Ying, X. X.; Guan, H. Q. Li, J. C. Magnolol-induced H460 cells death via autophagy but not apoptosis. Arch. Pharm. Res., 2007, 30(12), 1566-1574.
62. Rasul, A.; Yu, B.; Khan, M.; Zhang, K.; Iqbal, F.; Ma, T. Yang, H. Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via the mitochondrial and PI3K/Akt signaling pathways. Int. J. Oncol., 2012, 40(4), 1153-1161.
63. Yang, T. P.; Lee, H. J.; Ou, T. T.; Chang, Y. J. Wang, C. J. Mulberry Leaf Polyphenol Extract Induced Apoptosis Involving Regulation of Adenosine Monophosphate-Activated Protein Kinase/Fatty Acid Synthase in a p53-Negative Hepatocellular Carcinoma Cell. J. Agric. Food. Chem., 2012. In Press.
64. Acharya, B. R.; Bhattacharyya, S.; Choudhury, D. Chakrabarti, G. The microtubule depolymerizing agent naphthazarin induces both apoptosis and autophagy in A549 lung cancer cells. Apoptosis, 2011, 16(9), 924-939.
65. Jing, K.; Song, K. S.; Shin, S.; Kim, N.; Jeong, S.; Oh, H. R.; Park, J. H.; Seo, K. S.; Heo, J. Y.; Han, J.; Park, J. I.; Han, C.; Wu, T.; Kweon, G. R.; Park, S. K.; Yoon, W. H.; Hwang, B. D. Lim, K. Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy, 2011, 7(11), 1348-1358.
66. Wang, S. Y.; Yu, Q. J.; Bao, J. K. Liu, B. Polygonatum cyrtonema lectin, a potential antineoplastic drug targeting programmed cell death pathways. Biochem. Biophys. Res. Commun., 2011, 406(4), 497-500.
67. Liu, B.; Cheng, Y.; Bian, H. J. Bao, J. K. Molecular mechanisms of Polygonatum cyrtonema lectin-induced apoptosis and autophagy in cancer cells. Autophagy, 2009, 5(2), 253-255.
68. Liu, B.; Wu, J. M.; Li, J.; Liu, J. J.; Li, W. W.; Li, C. Y.; Xu, H. L. Bao, J. K. Polygonatum cyrtonema lectin induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras- Raf and PI3K-Akt signaling pathways. Biochimie, 2010, 92(12), 1934-1938.
69. Priyadarsini, R. V.; Vinothini, G.; Murugan, R. S.; Manikandan, P. Nagini, S. The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutr. Cancer, 2011, 63(2), 218-226.
70. Pietrocola, F.; Mariño, G.; Lissa, D.; Vacchelli, E.; Malik, S. A.; Niso-Santano, M.; Zamzami, N.; Galluzzi, L.; Maiuri, M. C. Kroemer, G. Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins. Cell Cycle, 2012, 11(20), 3851-3860.
71. Shakibaei, M.; Harikumar, K. B. Aggarwal, B. B. Resveratrol addiction: to die or not to die. Mol Nutr Food Res, 2009, 53(1), 115-128.
72. Maioli, E.; Torricelli, C. Valacchi, G. Rottlerin and cancer: novel evidence and mechanisms. The Scientific World Journal, 2012, 2012, 350826.
73. Valacchi, G.; Pecorelli, A.; Mencarelli, M.; Carbotti, P.; Fortino, V.; Muscettola, M. Maioli, E. Rottlerin: a multifaced regulator of keratinocyte cell cycle. Exp Dermatol., 2009, 18(6), 516-521.
74. Singh, B. N.; Kumar, D.; Shankar, S. Srivastava, R. K. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem. Pharmacol., 2012, 84(9), 1154-1163.
75. Duan, W. J.; Li, Q. S.; Xia, M. Y.; Tashiro, S.; Onodera, S. Ikejima, T. Silibinin activated ROS-p38-NF-_B positive feedback and induced autophagic death in human fibrosarcoma HT1080 cells. J. Asian Nat. Prod. Res., 2011, 13(1), 27-35.
76. Duan, W. J.; Li, Q. S.; Xia, M. Y.; Tashiro, S.; Onodera, S. Ikejima, T. Silibinin activated p53 and induced autophagic death in human fibrosarcoma HT1080 cells via reactive oxygen species-p38 and c-Jun N-terminal kinase pathways. Biol. Pharm. Bull., 2011, 34(1), 47-53.
77. Pan, M. H.; Hsieh, M. C.; Hsu, P. C.; Ho, S. Y.; Lai, C. S.; Wu, H.; Sang, S. Ho, C. T. 6-Shogaol suppressed lipopolysaccharideinduced up-expression of iNOS and COX-2 in murine macrophages. Mol. Nutr. Food Res., 2008, 52(12), 1467-1477.
78. Hung, J. Y.; Hsu, Y. L.; Li, C. T.; Ko, Y. C.; Ni, W. C.; Huang, M. S. Kuo, P. L. 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J. Agric. Food Chem., 2009, 57(20), 9809-9816.
79. Cruz, M.; Siden, Å.; Calaf, G.; Delwar, Z. Yakisich, J. S. The Stemness Phenotype model. ISRN Oncology, 2012, 2012, 392647.
80. Laks, D. R.; Visnyei, K. Kornblum, H. I. Brain tumor stem cells as therapeutic targets in models of glioma. Yonsei Med. J., 2010, 51(5), 633-640.
81. Vermeulen, L.; de Sousa E., Melo, F. Richel, D. J., Medema, J. P. The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol, 2012, 13(2), e83-89.
82. Cavazzoni, A.; Bonelli, M. A.; Fumarola, C.; La Monica, S.; Airoud, K.; Bertoni, R.; Alfieri, R. R.; Galetti, M.; Tramonti, S.; Galvani, E.; Harris, A. L.; Martin, L. A.; Andreis, D.; Bottini, A.; Generali, D. Petronini, P. G. Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett., 2012, 323(1), 77-87.
83. Ibanez, E.; Agliano, A.; Prior, C.; Nguewa, P.; Redrado, M.; Gonzalez-Zubeldia, I.; Plano, D.; Palop, J. A.; Sanmartin, C. Calvo, A. The Quinoline Imidoselenocarbamate EI201 Blocks the AKT/mTOR Pathway and Targets Cancer Stem Cells Leading to a Strong Antitumor Activity. Curr. Med. Chem., 2012, 19(18), 3031-3043.
84. Li, Y.; Kong, D.; Bao, B.; Ahmad, A. Sarkar, F. H. Induction of cancer cell death by isoflavone: the role of multiple signaling pathways. Nutrients, 2011, 3(10), 877-896.
85. Yakisich, J. S.; Ohlsson-Lindblom, I.; Siden, A. Cruz, M. H. Rapid inhibition of ongoing DNA synthesis in human glioma tissue by genistein. Oncol. Rep., 2009, 22(3), 569-574.
86. Yakisich, J. S.; Sidén, A.; Idoyaga Vargas, V.; Eneroth, P. Cruz, M. Early inhibition of DNA synthesis in the developing rat cerebral cortex by the purine analogues olomoucine and roscovitine. Biochem. Biophys. Res. Commun., 1998, 243(3), 674-647.
87. Kim, M. H.; Yoo, D. S.; Lee, S. Y.; Byeon, S. E.; Lee, Y. G.; Min, T.; Rho, H. S.; Rhee, M. H.; Lee, J. Cho, J. Y. The TRIF/TBK1/IRF-3 activation pathway is the primary inhibitory target of resveratrol, contributing to its broad-spectrum antiinflammatory effects. Pharmazie, 2011, 66(4), 293-300.
88. Liu, J.; Zhang, Y.; Qu, J.; Xu, L.; Hou, K.; Zhang, J.; Qu, X. Liu, Y. β-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis. BMC Cancer, 2011, 11, 183.
89. Liang, D.; Yang, M.; Guo, B.; Yang, L.; Cao, J. Zhang, X. HIF-1β induced by β-elemene protects human osteosarcoma cells from undergoing apoptosis. J. Cancer Res. Clin. Oncol., 2012, 138(11), 1865-1877.
90. Klappan, A. K.; Hones, S.; Mylonas, I. Brüning, A. Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity. Histochem. Cell Biol., 2012, 137(1), 25-36.
91. Li, L. J.; Zhong, L. F.; Jiang, L. P.; Geng, C. Y. Zou, L.J. β- Elemene Radiosensitizes Lung Cancer A549 Cells by Enhancing DNA Damage and Inhibiting DNA Repair. Phytother Res., 2011, 25(7), 1095-1097.
92. Zhang, F.; Xu, L.; Qu, X.; Zhao, M.; Jin, B.; Kang, J.; Liu, Y. Hu, X. Synergistic antitumor effect of _-elemene and etoposide is mediated via induction of cell apoptosis and cell cycle arrest in non-small cell lung carcinoma cells. Mol. Med. Report, 2011, 4(6), 1189-1193.
93. Zhu, T.; Xu, Y.; Dong, B.; Zhang, J.; Wei, Z.; Xu, Y. Yao, Y. β- elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor _ and induces sensitization to cisplatin. Oncol Rep., 2011, 26(2), 405-413.
94. Li, Q. Q.; Wang, G.; Zhang, M.; Cuff, C. F.; Huang, L. Reed, E. beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis. Oncol Rep., 2009, 22(1), 161-170.
95. Zhao, J.; Li, Q. Q.; Zou, B.; Wang, G.; Li, X.; Kim, J. E.; Cuff, C. F.; Huang, L.; Reed, E. Gardner, K. In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma. Int. J. Oncol., 2007, 31(2), 241-252.
96. Lin, C. J.; Lee, C. C.; Shih, Y. L.; Lin, T. Y.; Wang, S. H.; Lin, Y. F. Shih, C. M. Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy. Free Radic Biol Med., 2012, 52(2), 377-391.
97. Yuan, Y.; Xue, X.; Guo, R. B.; Sun, X. L. Hu, G. Resveratrol Enhances the Antitumor Effects of Temozolomide in Glioblastoma via ROS-dependent AMPK-TSC-mTOR Signaling Pathway. CNS Neurosci. Ther., 2012, 18(7), 536-546.
98. He, X.; Wang, Y.; Zhu, J.; Orloff, M. Eng, C. Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycininduced AKT signaling. Cancer Lett., 2011, 301(2), 168-176.
99. Masuelli, L.; Marzocchella, L.; Focaccetti, C.; Tresoldi, I.; Palumbo, C.; Izzi, V.; Benvenuto, M.; Fantini, M.; Lista, F.; Tarantino, U.; Modesti, A.; Galvano, F. Bei, R. Resveratrol and diallyl disulfide enhance curcumin-induced sarcoma cell apoptosis. Front. Biosci., 2012, 17: 498-508.
100. Tak, J. K.; Lee, J. H. Park, J. W. Resveratrol and piperine enhance radiosensitivity of tumor cells. BMB Rep., 2012, 45(4), 242-246.
101. Fang, Y.; Demarco, V. G. Nicholl, M. B. Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis. Cancer Sci., 2012, 103(6), 1090-1098.
102. Rashid, A.; Liu, C.; Sanli, T.; Tsiani, E.; Singh, G.; Bristow, R. G.; Dayes, I.; Lukka, H.; Wright, J. Tsakiridis, T. Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways. Radiat Oncol., 2011, 6: 144.
103. Casanova, F.; Quarti, J.; da Costa, D. C.; Ramos, C. A.; da Silva, J. L. Fialho, E. Resveratrol chemosensitizes breast cancer cells to melphalan by cell cycle arrest. J. Cell. Biochem., 2012, 113(8), 2586-2596.
104. Al-Abd, A. M.; Mahmoud, A. M.; El-Sherbiny, G. A.; El-Moselhy, M. A.; Nofal, S. M.; El-Latif, H. A.; El-Eraky, W. I. El-Shemy, H. A. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro. Cell Prolif., 2011, 44(6), 591-601.
105. Kai, L. Levenson, A. S. Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells. Anticancer Res., 2011, 31(10), 3323-3330.
106. Cheong, J. W.; Min, Y. H.; Eom, J. I.; Kim, S. J.; Jeung, H. K. Kim, J. S. Inhibition of CK2{alpha} and PI3K/Akt synergistically induces apoptosis of CD34+CD38- leukaemia cells while sparing haematopoietic stem cells. Anticancer Res, 2010, 30(11), 4625-4634.
107. Gallmeier, E.; Hermann, P. C.; Mueller, M. T.; Machado, J. G.; Ziesch, A.; De Toni, E. N.; Palagyi, A.; Eisen, C.; Ellwart, J. W.; Rivera, J.; Rubio-Viqueira, B.; Hidalgo, M.; Bunz, F.; Göke, B. Heeschen, C. Inhibition of ataxia telangiectasia- and Rad3-related function abrogates the in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of the CD133(+) tumorinitiating cell fraction. Stem Cells, 2011, 29(3), 418-429.
108. Fong, D.; Yeh, A.; Naftalovich, R.; Choi, T. H. Chan, M. M. Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals. Cancer Lett., 2010, 293(1), 65-72.
109. Zhang, L.; Li, L.; Jiao, M.; Wu, D.; Wu, K.; Li, X.; Zhu, G.; Yang, L.; Wang, X.; Hsieh, J. T. He, D. Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett., 2012, 323(1), 48-57.
110. Montales, M. T.; Rahal, O. M.; Kang, J.; Rogers, T. J.; Prior, R. L.; Wu, X. Simmen, R. C. Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis, 2012, 33(3), 652-660.
111. Chang, W. W.; Hu, F. W.; Yu, C. C.; Wang, H. H.; Feng, H. P.; Lan, C.; Tsai, L. L. Chang, Y. C. Quercetin in elimination of tumor initiating stem-like and mesenchymal transformation property in head and neck cancer. Head Neck, 2012, 35(3), 413-419.
112. Adikrisna, R.; Tanaka, S.; Muramatsu, S.; Aihara, A.; Ban, D.; Ochiai, T.; Irie, T.; Kudo, A.; Nakamura, N.; Yamaoka, S. Arii, S. Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology, 2012, 143(1), 234-245. e237.
113. Srivastava, R. K.; Tang, S. N.; Zhu, W.; Meeker, D. Shankar, S. Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells. Front. Biosci. (Elite Ed), 2011, 3, 515-528.
114. Zhuang, W.; Li, B.; Long, L.; Chen, L.; Huang, Q. Liang, Z. Induction of autophagy promotes differentiation of gliomainitiating cells and their radiosensitivity. Int J Cancer, 2011, 129(11), 2720-2731.
115. Pandey, P. R.; Okuda, H.; Watabe, M.; Pai, S. K.; Liu, W.; Kobayashi, A.; Xing, F.; Fukuda, K.; Hirota, S.; Sugai, T.; Wakabayashi, G.; Koeda, K.; Kashiwaba, M.; Suzuki, K.; Chiba, T.; Endo, M.; Fujioka, T.; Tanji, S.; Mo, Y.Y.; Cao, D.; Wilber, A. C. Watabe, K. Resveratrol suppresses growth of cancer stemlike cells by inhibiting fatty acid synthase. Breast Cancer Res. Treat., 2011, 130(2), 387-398.
116. Kao, C. L.; Huang, P. I.; Tsai, P. H.; Tsai, M. L.; Lo, J. F.; Lee, Y. Y.; Chen, Y. J.; Chen, Y. W. Chiou, S. H. Resveratrol-induced apoptosis and increased radiosensitivity in CD133-positive cells derived from atypical teratoid/rhabdoid tumor. Int. J. Radiat. Oncol. Biol. Phys., 2009, 74(1), 219-28.
117. Wang, J. Y.; Chang, C. C.; Chiang, C. C.; Chen, W. M. Hung, S. C. Silibinin suppresses the maintenance of colorectal cancer stem-like cells by inhibiting PP2A/AKT/mTOR pathways. J Cell Biochem., 2012, 113(5), 1733-1743.
118. Zhu, T.; Zhao, Y.; Zhang, J.; Li, L.; Zou, L.; Yao, Y. Xu, Y. ß- Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. Int J Oncol., 2011, 38(2), 419-426.
119. Yao, Y. Q.; Ding, X.; Jia, Y. C.; Huang, C. X.; Wang, Y. Z. Xu, Y. H. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett., 2008, 264(1), 127-134.
120. Zhao, Y. S.; Zhu, T. Z.; Chen, Y. W.; Yao, Y. Q.; Wu, C. M.; Wei, Z. Q.; Wang, W. Xu, Y. H. β-elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells. J Neurooncol., 2012, 107(2), 307-314.
121. Wang, Y. Fang, M. Y. Effect of ginseng saponin, arsenic trioxide, beta-elemene combined with CTX on telomere-telomerase system in K562 cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi., 2006, 14(6), 1089-1095.
122. Leon-Galicia, I.; Diaz-Chavez, J.; Garcia-Villa, E.; Uribe-Figueroa, L.; Hidalgo-Miranda, A.; Herrera, L. A.; Alvarez-Rios, E.; Garcia-Mena, J. Gariglio, P. Resveratrol induces downregulation of DNA repair genes in MCF-7 human breast cancer cells. Eur. J. Cancer Prev., 2012, 22(1), 11-20.
123. Lin, X.; Wu, G.; Huo, W. Q.; Zhang, Y. Jin, F. S. Resveratrol induces apoptosis associated with mitochondrial dysfunction in bladder carcinoma cells. Int. J. Urol., 2012, 19(8), 757-64.
124. Iqbal, M. A. Bamezai, R. N. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One., 2012, 7(5), e36764.
125. Park, S. A.; Na, H. K. Surh, Y. J. Resveratrol suppresses 4- hydroxyestradiol-induced transformation of human breast epithelial cells by blocking I_B kinase_-NF-_B signalling. Free Radic. Res., 2012, 46(8), 1051-1057.
126. Mo, W.; Xu, X.; Xu, L.; Wang, F.; Ke, A.; Wang, X. Guo, C. Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology, 2011, 11(6), 601-609.
127. Zhang, W.; Wang, X. Chen, T. Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells. Cell Signal., 2012, 24(5), 1037-1046.
128. Wang, Z.; Li, W.; Meng, X. Jia, B. Resveratrol induces gastric cancer cell apoptosis via reactive oxygen species, but independent of sirtuin1. Clin. Exp. Pharmacol. Physiol., 2012, 39(3), 227-232.
129. Roy, S. K.; Chen, Q.; Fu, J.; Shankar, S. Srivastava, R. K. Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS One, 2011, 6(9), e25166.
130. Huang, H.; Lin, H.; Zhang, X. Li, J. Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-βB-dependent pathway. Oncol. Rep., 2012, 27(6), 2050-2056.
131. Lee, K. A.; Lee, Y. J.; Ban, J. O.; Lee, Y. J.; Lee, S. H.; Cho, M. K.; Nam, H. S.; Hong, J. T. Shim, J. H. The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1. Int J Mol Med., 2012, 30(1), 21-27.
132. Zhao, W.; Bao, P.; Qi, H. You, H. Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPCA- 1/CDDP cells. Oncol Rep., 2010, 23(1), 279-286.