MTORC1 activity as a determinant of cancer risk - Rationalizing the cancer-preventive effects of adiponectin, metformin, rapamycin, and low-protein vegan diets

Medical Hypotheses

Volumn 77, Issue 4, 2011, Pages 642-648

  McCarty, Mark F ^a  

^a NutriGuard Research   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPONECTIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INITIATION FACTOR 4E; MESSENGER RNA; METFORMIN; MTORC1 PROTEIN; PROTEIN SERINE THREONINE KINASE; RAPAMYCIN; STAT3 PROTEIN; UNCLASSIFIED DRUG;

ANGIOGENESIS; APOPTOSIS; ARTICLE; CANCER INVASION; CANCER PREVENTION; CANCER RISK; CELL PROLIFERATION; CLINICAL ASSESSMENT; DOWN REGULATION; DRUG TARGETING; GENE OVEREXPRESSION; GRAFT RECIPIENT; HUMAN; NONHUMAN; PROTEIN BLOOD LEVEL; PROTEIN RESTRICTION; REGULATORY MECHANISM; TUMOR PROMOTION; UPREGULATION;

ADIPONECTIN; DIET, VEGETARIAN; DIETARY PROTEINS; DOWN-REGULATION; HUMANS; METFORMIN; NEOPLASMS; PROTEINS; SIROLIMUS;

EID: 80052616521     PISSN: 03069877     EISSN: 15322777     Source Type: Journal    
DOI: 10.1016/j.mehy.2011.07.004     Document Type: Article

References (110)

1. Petridou E., Mantzoros C., Dessypris N., Koukoulomatis P., Addy C., Voulgaris Z., et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab 2003, 88(3):993-997.
2. Mantzoros C., Petridou E., Dessypris N., Chavelas C., Dalamaga M., Alexe D.M., et al. Adiponectin and breast cancer risk. J Clin Endocrinol Metab 2004, 89(3):1102-1107.
3. Wei E.K., Giovannucci E., Fuchs C.S., Willett W.C., Mantzoros C.S. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 2005, 97(22):1688-1694.
4. Kelesidis I., Kelesidis T., Mantzoros C.S. Adiponectin and cancer: a systematic review. Br J Cancer 2006, 94(9):1221-1225.
5. Li H., Stampfer M.J., Mucci L., Rifai N., Qiu W., Kurth T., et al. A 25-year prospective study of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clin Chem 2010, 56(1):34-43.
6. Evans J.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R., Morris A.D. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005, 330(7503):1304-1305.
7. Libby G., Donnelly L.A., Donnan P.T., Alessi D.R., Morris A.D., Evans J.M. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009, 32(9):1620-1625.
8. Currie C.J., Poole C.D., Gale E.A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009, 52(9):1766-1777.
9. Landman G.W., Kleefstra N., van Hateren K.J., Groenier K.H., Gans R.O., Bilo H.J. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 2010, 33(2):322-326.
10. Kahan B.D., Yakupoglu Y.K., Schoenberg L., Knight R.J., Katz S.M., Lai D., et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation 2005, 80(6):749-758.
11. Campistol J.M., Eris J., Oberbauer R., Friend P., Hutchison B., Morales J.M., et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006, 17(2):581-589.
12. Geissler E.K. The impact of mTOR inhibitors on the development of malignancy. Transplant Proc 2008, 40(10 Suppl):S32-S35.
13. Campbell T.C., Junshi C. Diet and chronic degenerative diseases: perspectives from China. Am J Clin Nutr 1994, 59(5 Suppl):1153S-1161S.
14. Ngo T.H., Barnard R.J., Leung P.S., Cohen P., Aronson W.J. Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: possible mediators for the effects of diet and exercise on cancer cell survival. Endocrinology 2003, 144(6):2319-2324.
15. McCarty M.F. Insulin and IGF-I as determinants of low " Western" cancer rates in the rural third world. Int J Epidemiol 2004, 33(4):908-910.
16. McCarty M.F. Mortality from Western cancers rose dramatically among African-Americans during the 20th century: are dietary animal products to blame?. Med Hypotheses 2001, 57(2):169-174.
17. Kopelovich L., Fay J.R., Sigman C.C., Crowell J.A. The mammalian target of rapamycin pathway as a potential target for cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 2007, 16(7):1330-1340.
18. Avruch J., Long X., Ortiz-Vega S., Rapley J., Papageorgiou A., Dai N. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 2009, 296(4):E592-E602.
19. Guertin D.A., Stevens D.M., Thoreen C.C., Burds A.A., Kalaany N.Y., Moffat J., et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006, 11(6):859-871.
20. Sancak Y., Peterson T.R., Shaul Y.D., Lindquist R.A., Thoreen C.C., Bar-Peled L., et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 320(5882):1496-1501.
21. Inoki K., Li Y., Zhu T., Wu J., Guan K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002, 4(9):648-657.
22. Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A., Spooner E., et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007, 25(6):903-915.
23. Shaw R.J. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 2009, 196(1):65-80.
24. Sun Y., Fang Y., Yoon M.S., Zhang C., Roccio M., Zwartkruis F.J., et al. Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc Natl Acad Sci USA 2008, 105(24):8286-8291.
25. Chan E.Y. MTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Sci Signal 2009, 2(84):e51.
26. Cuervo A.M. Calorie restriction and aging: the ultimate " cleansing diet" J Gerontol A Biol Sci Med Sci 2008, 63(6):547-549.
27. Gingras A.C., Raught B., Gygi S.P., Niedzwiecka A., Miron M., Burley S.K., et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001, 15(21):2852-2864.
28. Silva R.L., Wendel H.G. MNK, EIF4E and targeting translation for therapy. Cell Cycle 2008, 7(5):553-555.
29. Culjkovic B., Topisirovic I., Borden K.L. Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle 2007, 6(1):65-69.
30. Graff J.R., Konicek B.W., Carter J.H., Marcusson E.G. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 2008, 68(3):631-634.
31. Miyagi Y., Sugiyama A., Asai A., Okazaki T., Kuchino Y., Kerr S.J. Elevated levels of eukaryotic translation initiation factor eIF-4E, mRNA in a broad spectrum of transformed cell lines. Cancer Lett 1995, 91(2):247-252.
32. Montanaro L., Pandolfi P.P. Initiation of mRNA translation in oncogenesis: the role of eIF4E. Cell Cycle 2004, 3(11):1387-1389.
33. Kentsis A., Topisirovic I., Culjkovic B., Shao L., Borden K.L. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA 2004, 101(52):18105-18110.
34. Rinker-Schaeffer C.W., Graff J.R., De B.A., Zimmer S.G., Rhoads R.E. Decreasing the level of translation initiation factor 4E with antisense RNA causes reversal of ras-mediated transformation and tumorigenesis of cloned rat embryo fibroblasts. Int J Cancer 1993, 55(5):841-847.
35. De B.A., Harris A.L. EIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 1999, 31(1):59-72.
36. Namba R., Young L.J., Abbey C.K., Kim L., Damonte P., Borowsky A.D., et al. Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ. Clin Cancer Res 2006, 12(8):2613-2621.
37. Wislez M., Spencer M.L., Izzo J.G., Juroske D.M., Balhara K., Cody D.D., et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 2005, 65(8):3226-3235.
38. Jiang H., Vogt P.K. Constitutively active Rheb induces oncogenic transformation. Oncogene 2008, 27(43):5729-5740.
39. Steeves M.A., Dorsey F.C., Cleveland J.L. Targeting the autophagy pathway for cancer chemoprevention. Curr Opin Cell Biol 2010, 22(2):218-225.
40. Musi N., Hirshman M.F., Nygren J., Svanfeldt M., Bavenholm P., Rooyackers O., et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002, 51(7):2074-2081.
41. Kim A.Y., Lee Y.S., Kim K.H., Lee J.H., Lee H.K., Jang S.H., et al. Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol 2010, 24(7):1441-1452.
42. Chen J., Zheng X.F., Brown E.J., Schreiber S.L. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA 1995, 92(11):4947-4951.
43. Hagner P.R., Mazan-Mamczarz K., Dai B., Corl S., Zhao X.F., Gartenhaus R.B. Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction. Blood 2009, 113(22):5526-5535.
44. Harp J.B., Goldstein S., Phillips L.S. Nutrition and somatomedin. XXIII. Molecular regulation of IGF-I by amino acid availability in cultured hepatocytes. Diabetes 1991, 40(1):95-101.
45. Fontana L., Weiss E.P., Villareal D.T., Klein S., Holloszy J.O. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 2008, 7(5):681-687.
46. McCarty M.F. Dietary saturate/unsaturate ratio as a determinant of adiposity. Med Hypotheses 2010, 75(1):14-16.
47. Rabinowitz D., Merimee T.J., Maffezzoli R., Burgess J.A. Patterns of hormonal release after glucose, protein, and glucose plus protein. Lancet 1966, 2(7461):454-456.
48. Frystyk J., Grofte T., Skjaerbaek C., Orskov H. The effect of oral glucose on serum free insulin-like growth factor-I and -II in health adults. J Clin Endocrinol Metab 1997, 82(9):3124-3127.
49. Song G., Ouyang G., Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005, 9(1):59-71.
50. Shaw R.J. MTOR signaling: RAG GTPases transmit the amino acid signal. Trends Biochem Sci 2008, 33(12):565-568.
51. Howarth K.R., Moreau N.A., Phillips S.M., Gibala M.J. Coingestion of protein with carbohydrate during recovery from endurance exercise stimulates skeletal muscle protein synthesis in humans. J Appl Physiol 2009, 106(4):1394-1402.
52. Cota D., Proulx K., Smith K.A., Kozma S.C., Thomas G., Woods S.C., et al. Hypothalamic mTOR signaling regulates food intake. Science 2006, 312(5775):927-930.
53. Food and Agricultural Organization UN. Amino-acid content of foods and biological data on proteins. Rome: 1970.
54. Norton L.E., Layman D.K., Bunpo P., Anthony T.G., Brana D.V., Garlick P.J. The leucine content of a complete meal directs peak activation but not duration of skeletal muscle protein synthesis and mammalian target of rapamycin signaling in rats. J Nutr 2009, 139(6):1103-1109.
55. Frid A.H., Nilsson M., Holst J.J., Bjorck I.M. Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 2005, 82(1):69-75.
56. Melnik B.C. Milk-the promoter of chronic Western diseases. Med Hypotheses 2009, 72(6):631-639.
57. Frattaroli J., Weidner G., Dnistrian A.M., Kemp C., Daubenmier J.J., Marlin R.O., et al. Clinical events in prostate cancer lifestyle trial: results from two years of follow-up. Urology 2008, 72(6):1319-1323.
58. McCarty M.F. Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses 2004, 63(2):334-339.
59. Goodwin P.J., Ligibel J.A., Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol 2009, 27(20):3271-3273.
60. Jiralerspong S., Palla S.L., Giordano S.H., Meric-Bernstam F., Liedtke C., Barnett C.M., et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009, 27(20):3297-3302.
61. Hirsch H.A., Iliopoulos D., Tsichlis P.N., Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009, 69(19):7507-7511.
62. Mondesire W.H., Jian W., Zhang H., Ensor J., Hung M.C., Mills G.B., et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 2004, 10(20):7031-7042.
63. Tam K.H., Yang Z.F., Lau C.K., Lam C.T., Pang R.W., Poon R.T. Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. Cancer Lett 2009, 273(2):201-209.
64. Shi Y., Yan H., Frost P., Gera J., Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005, 4(10):1533-1540.
65. Tremblay F., Lavigne C., Jacques H., Marette A. Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 2007, 27:293-310.
66. Zakikhani M., Blouin M.J., Piura E., Pollak M.N. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010, 123(1):271-279.
67. Ning J., Clemmons D.R. AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol Endocrinol 2010, 24(6):1218-1229.
68. Dunn S.E., Hardman R.A., Kari F.W., Barrett J.C. Insulin-like growth factor 1(IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. Cancer Res 1997, 57(13):2687-2693.
69. Grothey A., Voigt W., Schober C., Muller T., Dempke W., Schmoll H.J. The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis, and chemoresistance in solid tumors. J Cancer Res Clin Oncol 1999, 125(3-4):166-173.
70. Gooch J.L., Van Den Berg C.L., Yee D. Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death-proliferative and anti-apoptotic effects. Breast Cancer Res Treat 1999, 56(1):1-10.
71. Liu Y.C., Leu C.M., Wong F.H., Fong W.S., Chen S.C., Chang C., et al. Autocrine stimulation by insulin-like growth factor I is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells. J Biomed Sci 2002, 9(6 Pt. 2):665-674.
72. Min Y., Adachi Y., Yamamoto H., Imsumran A., Arimura Y., Endo T., et al. Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts. Gut 2005, 54(5):591-600.
73. Yun H., Lee M., Kim S.S., Ha J. Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. J Biol Chem 2005, 280(11):9963-9972.
74. Phoenix K.N., Vumbaca F., Claffey K.P. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 2009, 113(1):101-111.
75. Harhaji-Trajkovic L., Vilimanovich U., Kravic-Stevovic T., Bumbasirevic V., Trajkovic V. AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. J Cell Mol Med 2009, 13(9B):3644-3654.
76. Xiong H.Y., Guo X.L., Bu X.X., Zhang S.S., Ma N.N., Song J.R., et al. Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell. Cancer Lett 2010, 288(1):68-74.
77. Livesey K.M., Tang D., Zeh H.J., Lotze M.T. Autophagy inhibition in combination cancer treatment. Curr Opin Investig Drugs 2009, 10(12):1269-1279.
78. Amaravadi R.K., Lippincott-Schwartz J., Yin X.M., Weiss W.A., Takebe N., Timmer W., et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011, 17(4):654-666.
79. Lin C.J., Malina A., Pelletier J. C-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. Cancer Res 2009, 69(19):7491-7494.
80. Zhu N., Gu L., Findley H.W., Zhou M. Transcriptional repression of the eukaryotic initiation factor 4E gene by wild type p53. Biochem Biophys Res Commun 2005, 335(4):1272-1279.
81. Tamburini J., Green A.S., Bardet V., Chapuis N., Park S., Willems L., et al. Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia. Blood 2009, 114(8):1618-1627.
82. Azar R., Najib S., Lahlou H., Susini C., Pyronnet S. Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1. Cell Mol Life Sci 2008, 65(19):3110-3117.
83. Graff J.R., Konicek B.W., Vincent T.M., Lynch R.L., Monteith D., Weir S.N., et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest 2007, 117(9):2638-2648.
84. Rodriguez-Pascual J., Cheng E., Maroto P., Duran I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 2010, 21(5):478-486.
85. Dong K., Wang R., Wang X., Lin F., Shen J.J., Gao P., et al. Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells. Breast Cancer Res Treat 2009, 113(3):443-456.
86. Tamburini J., Green A.S., Chapuis N., Bardet V., Lacombe C., Mayeux P., et al. Targeting translation in acute myeloid leukemia: a new paradigm for therapy?. Cell Cycle 2009, 8(23):3893-3899.
87. Culjkovic B., Borden K.L. Understanding and targeting the eukaryotic translation initiation factor eIF4E in head and neck cancer. J Oncol 2009, 2009:981679.
88. Westman B., Beeren L., Grudzien E., Stepinski J., Worch R., Zuberek J., et al. The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro. RNA 2005, 11(10):1505-1513.
89. Yan Y., Svitkin Y., Lee J.M., Bisaillon M., Pelletier J. Ribavirin is not a functional mimic of the 7-methyl guanosine mRNA cap. RNA 2005, 11(8):1238-1244.
90. Kentsis A., Volpon L., Topisirovic I., Soll C.E., Culjkovic B., Shao L., et al. Further evidence that ribavirin interacts with eIF4E. RNA 2005, 11(12):1762-1766.
91. Aggarwal B.B. Nuclear factor-kappaB: the enemy within. Cancer Cell 2004, 6(3):203-208.
92. McCarty M.F., Block K.I. Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther 2006, 5(3):252-268.
93. Arlt A., Schafer H. NFkappaB-dependent chemoresistance in solid tumors. Int J Clin Pharmacol Ther 2002, 40(8):336-347.
94. Singh R.P., Mallikarjuna G.U., Sharma G., Dhanalakshmi S., Tyagi A.K., Chan D.C., et al. Oral silibinin inhibits lung tumor growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor kappaB-mediated inducible chemoresistance. Clin Cancer Res 2004, 10(24):8641-8647.
95. Aggarwal B.B., Sethi G., Ahn K.S., Sandur S.K., Pandey M.K., Kunnumakkara A.B., et al. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann NY Acad Sci 2006, 1091:151-169.
96. Grivennikov S.I., Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 2010, 21(1):11-19.
97. Deng J., Grande F., Neamati N. Small molecule inhibitors of Stat3 signaling pathway. Curr Cancer Drug Targets 2007, 7(1):91-107.
98. Lee D.H., Iwanski G.B., Thoennissen N.H. Cucurbitacin: ancient compound shedding new light on cancer treatment. ScientificWorldJournal 2010, 10:413-418.
99. Ahn K.S., Sethi G., Sung B., Goel A., Ralhan R., Aggarwal B.B. Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. Cancer Res 2008, 68(11):4406-4415.
100. Kunnumakkara A.B., Nair A.S., Sung B., Pandey M.K., Aggarwal B.B. Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res 2009, 7(1):118-128.
101. Pandey M.K., Sung B., Aggarwal B.B. Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int J Cancer 2010, 127(2):282-292.
102. Shishodia S., Sethi G., Ahn K.S., Aggarwal B.B. Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. Biochem Pharmacol 2007, 74(1):118-130.
103. An M.J., Cheon J.H., Kim S.W., Kim E.S., Kim T.I., Kim W.H. Guggulsterone induces apoptosis in colon cancer cells and inhibits tumor growth in murine colorectal cancer xenografts. Cancer Lett 2009, 279(1):93-100.
104. Leeman-Neill R.J., Wheeler S.E., Singh S.V., Thomas S.M., Seethala R.R., Neill D.B., et al. Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3. Carcinogenesis 2009, 30(11):1848-1856.
105. Shishodia S., Aggarwal B.B. Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 2004, 279(45):47148-47158.
106. Singh R.P., Raina K., Deep G., Chan D., Agarwal R. Silibinin suppresses growth of human prostate carcinoma PC-3 orthotopic xenograft via activation of extracellular signal-regulated kinase 1/2 and inhibition of signal transducers and activators of transcription signaling. Clin Cancer Res 2009, 15(2):613-621.
107. Tyagi A., Singh R.P., Ramasamy K., Raina K., Redente E.F., Dwyer-Nield L.D., et al. Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage-associated cytokines and nuclear factor-kappaB and signal transducers and activators of transcription 3. Cancer Prev Res (Phila Pa) 2009, 2(1):74-83.
108. Singh R.P., Tyagi A., Sharma G., Mohan S., Agarwal R. Oral silibinin inhibits in vivo human bladder tumor xenograft growth involving down-regulation of survivin. Clin Cancer Res 2008, 14(1):300-308.
109. Kaur M., Velmurugan B., Tyagi A., Deep G., Katiyar S., Agarwal C., et al. Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther 2009, 8(8):2366-2374.
110. Candelaria M., Gallardo-Rincon D., Arce C., Cetina L., guilar-Ponce J.L., Arrieta O., et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 2007, 18(9):1529-1538.