Herbal therapeutics that block the oncogenic kinase PAK1: A practical approach towards PAK1-dependent diseases and longevity

Phytotherapy Research

Volumn 28, Issue 5, 2014, Pages 656-672

  Maruta, Hiroshi ^a  

^a NF TSC Cure Organisation   (Australia)

Author keywords

AIDS; Alzheimer's disease; cancer; curcumin; diabetes; King of Bitters; longevity; neurofibromatosis; PAK1; propolis; Thunder god vine; tuberous sclerosis

Indexed keywords

ANDROGRAPHOLIDE; ARTEPILLIN C; BERBERINE; BIO 30; CAFFEIC ACID PHENETHYL ESTER; CAPSAICIN; CAPSIATE; CURCUMIN; FARNOQUINONE; GLAUCARUBINONE; HERBACEOUS AGENT; MENAQUINONE 7; P21 ACTIVATED KINASE 1; P21 ACTIVATED KINASE 4; PLANT MEDICINAL PRODUCT; PROPOLIS; PTEROSTILBENE; RESVERATROL; SALIDROSIDE; TRIPTOLIDE; UNCLASSIFIED DRUG;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ALZHEIMER DISEASE; ANTINEOPLASTIC ACTIVITY; DEPRESSION; DRUG STRUCTURE; ENZYME ACTIVATION; ENZYME INHIBITION; HELICOBACTER INFECTION; HUMAN; HUNTINGTON CHOREA; INFLAMMATORY DISEASE; INFLUENZA; LEARNING DISORDER; LIFESPAN; LONGEVITY; MALARIA; NEUROFIBROMATOSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; REVIEW; SCHIZOPHRENIA; SOLID TUMOR; TUBEROUS SCLEROSIS;

ANIMALIA; CAENORHABDITIS ELEGANS; DROSOPHILA (GENUS); NEMATODA;

AIDS; ALZHEIMER'S DISEASE; CANCER; CURCUMIN; DIABETES; KING OF BITTERS; LONGEVITY; NEUROFIBROMATOSIS; PAK1; PROPOLIS; THUNDER GOD VINE; TUBEROUS SCLEROSIS;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; COMMUNICABLE DISEASES; CURCUMIN; HUMANS; INFLAMMATION; LONGEVITY; NEOPLASMS; P21-ACTIVATED KINASES; PHYTOTHERAPY; PLANTS, MEDICINAL; PROPOLIS;

EID: 84899492189     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.5054     Document Type: Review

References (148)

1. Adelstein RS, Conti MA,. 1975. Phosphorylation of platelet myosin increases actin-activated myosin ATPase activity. Nature 256: 597-8.
2. Allen KM, Gleeson JG, Bagrodia S, et al,. 1998. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 20: 25-30.
3. Allen JD, Jaffer ZM, Park SJ, et al,. 2009. p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood 113: 2695-705.
4. Anisimov V, Zabezhinski M, Popovich I, et al,. 2011. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10: 4230-6.
5. Apostol BL, Simmons DA, Zuccato C, et al,. 2008. CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice. Mol Cell Neurosci 39: 8-20.
6. Awale S, Li F, Onozuka H, et al,. 2008. Constituents of Brazilian red propolis and their preferential cytotoxic activity against human pancreatic PANC-1 cancer cell line in nutrient-deprived condition. Bioorg Med Chem 16: 181-9.
7. Baek HY, Lim JW, Kim H,. 2007. Interaction between the Helicobacter pylori CagA and alpha-Pix in gastric epithelial AGS cells. Ann N Y Acad Sci 1096: 18-23.
8. Beevers CS, Chen L, Liu L, et al,. 2009. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res 69: 1000-8.
9. Beutler JA, Kang MI, Robert F, et al,. 2009. Quassinoid inhibition of AP-1 function does not correlate with cytotoxicity or protein synthesis inhibition. J Nat Prod 72: 503-6.
10. Bienvenu T, des Portes V, McDonell N, et al. 2000. Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. Am J Med Genet 93: 294-8.
11. Brandt J,. 1928. In: The Grape Cure. Jushua Tree. Tree of Life Publication: CA. 1096: 18-23.
12. Brusq JM, Ancellin N, Grondin P, et al,. 2006. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 47: 1281-8.
13. Cai XZ, Wang J, Li XD, Wang GL,. 2009. Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression. Cancer Biol Ther 8: 1360-8.
14. Carling D,. 2004. The AMP-activated protein kinase cascade - a unifying system for energy control. Trends Biochem Sci 29: 18-24.
15. Castelletti D, Fiaschetti G, Di Dato V, et al,. 2010. The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. Mol Cancer Ther 9: 3145-57.
16. Chacko S, Conti MA, Adelstein RS,. 1977. Effect of phosphorylation of smooth muscle myosin on actin activation and Ca2+ regulation. Proc Natl Acad Sci U S A 74: 129-33.
17. Chang KS, Gao C, Wang LC,. 1990. Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Lett 55: 103-8.
18. Chang J, Rimando A, Pallas M, et al,. 2012. Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's disease. Neurobiol Aging 33: 2062-71.
19. Chen SY, Huang PH, Cheng HJ,. 2011. Disrupted-in-Schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci U S A 108: 5861-6.
20. Chugh R, Sangwan V, Patil SP, et al,. 2012. A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer. Sci Transl Med 4: 156ra139.
21. Collett MS, Erikson RL,. 1978. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc Natl Acad Sci U S A 75: 2021-4.
22. Conrad KE, Gutierrez-Hartmann A,. 1992. The RAS and PKA pathways are mutually antagonistic in regulating rat prolactin promoter activity. Oncogene 7: 1279-86.
23. Deguchi A, Miyoshi H, Kojima Y, et al,. 2010. LKB1 suppresses p21-activated kinase-1 (PAK1) by phosphorylation of Thr109 in the p21-binding domain. J Biol Chem 285: 18283-90.
24. Demestre M, Messerli SM, Celli N, et al,. 2009. CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytother Res 23: 226-30.
25. Dorman J, Albinder B, Shroyer T, Kenyon C,. 1995. The AGE-1 and DAF-2 genes function in a common pathway to control the lifespan of C. elegans. Genet. 141: 1399-406.
26. Easwaran V, Lee SH, Inge L, et al,. 2003. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 63: 3145-53.
27. Edwards DC, Sanders LC, Bokoch GM, Gill GN,. 1999. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1: 253-9.
28. Eom HS, Lee EJ, Yoon BS, Yoo BS,. 2010. Propolis inhibits the proliferation of human leukaemia HL-60 cells by inducing apoptosis through the mitochondrial pathway. Nat Prod Res 24: 375-86.
29. Eriguchi M, Mizuta H, Luo S, et al,. 2010. alpha Pix enhances mutant huntingtin aggregation. J Neurol Sci. 290: 80-5.
30. Evans DA, Funkenstein HH, Albert MS, et al,. 1989. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA 262: 2551-6.
31. Friedman D, Johnson T,. 1988. A Mutation in the Age-1 Gene in C. elegans Lengthens Life and Reduces Hermaphrodite Fertility. Genetics 118: 75-86.
32. Fuliang HU, Hepburn HR, Xuan H, et al,. 2005. Effects of propolis on blood glucose, blood lipid and free radicals in rats with diabetes mellitus. Pharmacol Res 51: 147-52.
33. Ghosh PC, Larrahondo JE, LeQuesne PW, Raffauf RF,. 1977. Antitumor plants. IV. Constituents of Simarouba versicolor. Lloydia 40: 364-9.
34. Greer EL, Oskoui PR, Banko MR, et al,. 2007. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282: 30107-19.
35. Grunberger D, Banerjee R, Eisinger K, et al,. 1988. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 44: 230-2.
36. Hara K, Maruki Y, Long X, et al,. 2002. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110: 177-89.
37. zur Hausen H,. 1989. Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res 49: 4677-81.
38. Hayashi ML, Rao BS, Seo JS, et al,. 2007. Inhibition of PAK rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A 104: 11489-94.
39. Hashimoto H, Messerli SM, Sudo T, Maruta H,. 2009. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther 3: 243-6.
40. He H, Maruta H,. 2013. Oncogenicty of PAKs and their substrates. In PAKs, RAC/CDC42 (p21)-activated kinases: towards the cure of cancers and other PAK-dependent diseases, (Ed., Maruta H,), Elsevier: Oxford, 23-51.
41. He H, Hirokawa Y, Levitzki A, Maruta H,. 2000. An anti-Ras cancer potential of PP1, an inhibitor specific for Src family kinases: in vitro and in vivo studies. Cancer J 6: 243-8.
42. He H, Hirokawa Y, Manser E, et al,. 2001. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Cancer J 7: 191-202.
43. He H, Hirokawa Y, Gazit A, et al,. 2004. The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. Cancer Biol Ther 3: 96-101.
44. Heredia L, Helguera P, de Olmos S, et al,. 2006. Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. J Neurosci 26: 6533-42.
45. Hirokawa Y, Tikoo A, Huynh J, et al,. 2004. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J 10: 20-6.
46. Hirokawa Y, Nheu T, Grimm K, et al,. 2006. Sichuan pepper extracts block the PAK1/cyclin D1 pathway and the growth of NF1-deficient cancer xenograft in mice. Cancer Biol Ther 5: 305-9.
47. Hirokawa Y, Levitzki A, Lessene G, et al,. 2007. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Cancer Lett 245: 242-51.
48. Hodges AK, Li S, Maynard J, et al,. 2001. Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Hum Mol Genet 10: 2899-905.
49. Howitz KT, Bitterman KJ, Cohen HY, et al,. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-6.
50. Hwang JT, Park IJ, Shin JI, Lee YK,. 2005. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 338: 694-9.
51. Hyman SL, Arthur Shores E, North KN,. 2006. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol 48: 973-7.
52. Ibe S, Kumada K, Yoshida K, Otobe K,. 2013. Natto (fermented soybean) extract extends the adult lifespan of Caenorhabditis elegans. Biosci Biotechnol Biochem 77: 392-4.
53. Iida T, Moriyama T, Kobata K, Morita A,. 2003. TRPV1 activation and induction of nociceptive response by a non-pungent capsaicin-like compound, capsiate. Neuropharmacology 44: 958-67.
54. Jang M, Cai L, Udeani GO, et al,. 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275: 218-20.
55. Jia K, Chen D, Riddle D,. 2004. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131: 3897-906.
56. Jing F, Mogi M, Sakata A, et al. 2012. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory. J Cereb Blood Flow Metab 32: 248-55.
57. Kenerson H, Dundon TA, Yeung RS,. 2005. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res 57: 67-75.
58. Kenyon C,. 2010. A pathway that links reproductive status to lifespan in C. elegans. Ann N Y Acad Sci 1204: 156-62.
59. Khare V, Lyakhovich A, Dammann K, Lang M,. 2012. Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Biochem Pharmacol in press.
60. Kimoto T, Arai S, Kohguchi M, Aga M,. 1998. Apoptosis and suppression of tumor growth by artepillin C extracted from Brazilian propolis. Cancer Detect Prev 22: 506-15.
61. Kiosses WB, Hood J, Yang S, et al,. 2002. A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ Res 90: 697-702.
62. Knapp S,. 2013. 3D structure and physiological regulation of PAKs. In PAKs, RAC/CDC42 (p21)-activated kinases: towards the cure of cancers and other PAK-dependent diseases, (Ed., Maruta H,), Elsevier: Oxford, 137-148.
63. Krautkrämer E, Giese SI, Gasteier JE, et al,. 2004. Human immunodeficiency virus type 1 Nef activates p21-activated kinase via recruitment into lipid rafts. J Virol 78: 4085-97.
64. Kulkarni SK, Dhir A,. 2010. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 24: 317-24.
65. Kusters JG, van Vliet AH, Kuipers EJ,. 2006. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19: 449-90.
66. Lee ES, Uhm KO, Lee YM, et al,. 2007. CAPE (caffeic acid phenethyl ester) stimulates glucose uptake through AMPK (AMP-activated protein kinase) activation in skeletal muscle cells. Biochem Biophys Res Commun 361: 854-8.
67. Lee YC, Lin HH, Hsu CH, et al,. 2010. Inhibitory effects of andrographolide on migration and invasion in human non-small cell lung cancer A549 cells via down-regulation of PI3K/Akt signaling pathway. Eur J Pharmacol 632: 23-32.
68. Lei M, Lu W, Meng W, et al,. 2000. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 102: 387-97.
69. Li L, Braiteh FS, Kurzrock R,. 2005. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104: 1322-31.
70. Li HB, Ge YK, Zheng XX, Zhang L,. 2008. Salidroside stimulated glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase. Eur J Pharmacol 588: 165-9.
71. Liao VH, Yu CW, Chu YJ, et al,. 2011. Curcumin-mediated lifespan extension in C. elegans. Mech Ageing Dev. 132: 480-7.
72. Lin YJ, Seroude L, Benzer S,. 1998. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282: 943-6.
73. Lin VC, Tsai YC, Lin JN, et al,. 2012. Activation of AMPK by pterostilbene suppresses lipogenesis and cell-cycle progression in p53 positive and negative human prostate cancer cells. J Agric Food Chem 60: 6399-407.
74. Lithgow G, White T, Hinerfeld D, Johnson T,. 1994. Thermotolerance of a long-lived mutant of C. elegans. J Gerontol 49, B270-6.
75. Liu W, Nakamura H, Yamamoto T, et al,. 2007. Vitamin K2 inhibits the proliferation of HepG2 cells by up-regulating the transcription of p21 gene. Hepatol Res 37: 360-5.
76. Liu Y, Wang L, Wu Y, et al,. 2013. Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway. Toxicology 304: 120-31.
77. Luo S, Rubinsztein DC,. 2009. Huntingtin promotes cell survival by preventing Pak2 cleavage. J Cell Sci 122: 875-85.
78. Ma QL, Yang F, Frautschy SA, et al. 2012. PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cell Logist 2: 117-125.
79. Mach CM, Mathew L, Mosley SA, et al,. 2009. Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model. Anticancer Res 29: 1895-9.
80. Manning BD, Cantley LC,. 2003. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28: 573-6.
81. Manser E, Leung T, Salihuddin H, et al,. 1993. A non-receptor tyrosine kinase that inhibits the GTPase activity of p21cdc42. Nature 363: 364-7.
82. Manser E, Leung T, Salihuddin H, et al,. 1994. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367: 40-6.
83. Manser E, Loo TH, Koh CG, et al,. 1998. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol Cell 1: 183-92.
84. Maroney AC, Glicksman MA, Basma AN, et al,. 1998. Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J Neurosci 18: 104-11.
85. Maruta H,. 2011. Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1. Drug Discov Ther 5: 266-78.
86. Maruta H, Burgess AW,. 1994. Regulation of the Ras signalling network. Bioessays 16: 489-96.
87. Maruta H, Korn ED,. 1977. Acanthamoeba cofactor protein is a heavy chain kinase required for actin activation of the Mg2 + -ATPase activity of Acanthamoeba myosin I. J Biol Chem 252: 8329-32.
88. Maruta H, Messerli S, Jha R,. 2013. Natural or synthetic therapeutics that block PAK. In PAKs, RAC/CDC42(p21)-activated kinases; toward the cure of cancers and other PAK-dependent diseases, (Ed., Maruta H,). Elsevier: Oxford; 53-76.
89. Mazumdar A, Kumar R,. 2003. Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. FEBS Lett 535: 6-10.
90. Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni RB,. 2007. Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120: 279-88.
91. Mendoza-Naranjo A, Contreras-Vallejos E, Henriquez DR, et al,. 2012. Fibrillar Amyloid-beta1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase. J Alzheimers Dis 29: 63-7.
92. Messerli SM, Ahn MR, Kunimasa K, et al,. 2009. Artepillin C (ARC) in Brazilian green propolis selectively blocks oncogenic PAK1 signaling and suppresses the growth of NF tumors in mice. Phytother Res 23: 423-7.
93. Nasar S,. 1998. In: A beautiful mind. Simon and Schuster: New York, NY.
94. Nakazawa T, Yasuda T, Ueda J, Ohsawa K,. 2003. Antidepressant-like effects of apigenin and 2,4,5-trimethoxycinnamic acid from Perilla frutescens in the forced swimming test. Biol Pharm Bull 26: 474-80.
95. Nguyen DG, Wolff KC, Yin H, et al,. 2006. " UnPAKing" human immunodeficiency virus (HIV) replication: using small interfering RNA screening to identify novel cofactors and elucidate the role of group I PAKs in HIV infection. J Virol 80: 130-7.
96. Nheu TV, He H, Hirokawa Y, et al,. 2002. The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants. Cancer J 8: 328-36.
97. Nheu T, He H, Hirokawa Y, Walker F, et al,. 2004. PAK is essential for RAS-induced upregulation of cyclin D1 during the G1 to S transition. Cell Cycle 3: 71-4.
98. Nishida K, Komiyama T, Miyazawa S, et al,. 2004. Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50: 3365-76.
99. Noelker C, Bacher M, Gocke P, et al,. 2005. The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity. Neurosci Lett 383: 39-43.
100. Pan W, Yang H, Cao C, et al,. 2008. AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncol Rep 20: 1553-9
101. Pascua PN, Lee JH, Song MS, et al,. 2011. Role of the p21-activated kinases (PAKs) in influenza A virus replication. Biochem Biophys Res Commun 414: 569-74.
102. Peng WH, Lo KL, Lee YH, et al,. 2007. Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sci 81: 933-8.
103. Peng C, Zuo Y, Kwan KM, et al,. 2012. Blueberry extract prolongs lifespan of Drosophila melanogaster. Exp Gerontol 47: 170-8.
104. Perfumi M, Mattioli L,. 2007. Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice. Phytother Res 21: 37-43.
105. Pietsch K, Saul N, Chakrabarti S, et al,. 2011. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology 12: 329-47.
106. Plas DR, Thompson CB,. 2003. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278: 12361-6.
107. Potter GA, Patterson LH, Wanogho E, et al,. 2002. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br J Cancer 86: 774-8.
108. Prudêncio M, Rodrigues CD, Hannus M, et al,. 2008. Kinome-wide RNAi screen implicates at least 5 host hepatocyte kinases in Plasmodium sporozoite infection. PLoS Pathog 4: e1000201.
109. Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P, Minden A,. 2001. Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol Cell Biol 21: 3523-33.
110. Renkema GH, Manninen A, Mann DA, et al,. 1999. Identification of the Nef-associated kinase as p21-activated kinase 2. Curr Biol 9: 1407-10.
111. Rider L, Shatrova A, Feener EP, et al,. 2007. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem 282: 30985-96.
112. Rubinsztein DC, Carmichael J,. 2003. Huntington's disease: molecular basis of neurodegeneration. Expert Rev Mol Med 5: 1-21.
113. Saimaru H, Orihara Y,. 2010. Biosynthesis of acteoside in cultured cells of Olea europaea. J Nat Med 64: 139-45.
114. Sawai ET, Baur A, Struble H, et al,. 1994. Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. Proc Natl Acad Sci U S A 91: 1539-43.
115. Sawai ET, Khan IH, Montbriand PM, et al,. 1996. Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques. Curr Biol 6: 1519-27.
116. Sefton BM, Hunter T, Ball EH, Singer SJ,. 1981. Vinculin: a cytoskeletal target of the transforming protein of Rous sarcoma virus. Cell 24: 165-74.
117. Shaw RJ, Kosmatka M, Bardeesy N, et al,. 2004. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101: 3329-35.
118. Shibayama-Imazu T, Sakairi S, Watanabe A, et al,. 2003. Vitamin K(2) selectively induced apoptosis in ovarian TYK-nu and pancreatic MIA PaCa-2 cells out of eight solid tumor cell lines through a mechanism different from geranylgeraniol. J Cancer Res Clin Oncol 129: 1-11.
119. Shin DH, Kim OH, Jun HS, Kang MK,. 2008. Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway. Exp Mol Med 40: 486-94.
120. Shuai Y, Yisi Zhang Y, Gao L, Zhong Y., 2011. Stress Resistance Conferred by Neuronal Expression of Dominant-Negative Rac in Adult Drosophila melanogaster. J Neurogenet 25: 35-9.
121. Sicard A, Semblat JP, Doerig C, et al,. 2011. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cell Microbiol 13: 836-45.
122. Singh M, Singh N,. 2011. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells. Mol Cell Biochem 347: 1-11.
123. Skopińska-Rózewska E, Malinowski M, Wasiutyński A, et al,. 2008. The influence of Rhodiola quadrifida 50% hydro-alcoholic extract and salidroside on tumor-induced angiogenesis in mice. Pol J Vet Sci 11: 97-104.
124. Steckelings UM, Larhed M, Hallberg A, Widdop RE, et al,. 2011. Non-peptide AT2-receptor agonists. Curr Opin Pharmacol 11: 187-92.
125. Stehelin D, Varmus HE, Bishop JM, Vogt PK,. 1976. Nature (London) 260: 170-3.
126. Sun H, King AJ, Diaz HB, Marshall MS,. 2000. Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak. Curr Biol 10: 281-4.
127. Tang Y, Chen Z, Ambrose D, et al,. 1997. Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol Cell Biol 17: 4454-64.
128. Tang Y, Marwaha S, Rutkowski JL, et al,. 1998. A role for Pak protein kinases in Schwann cell transformation. Proc Natl Acad Sci U S A 95: 5139-44.
129. Tang T, Targan SR, Li ZS, et al,. 2011. Randomised clinical trial: herbal extract HMPL-004 in active ulcerative colitis-a double-blind comparison with sustained release mesalazine. Aliment Pharmacol Ther 33: 194-202.
130. Trager W, Polonsky J,. 1981. Antimalarial activity of quassinoids against chloroquine-resistant Plasmodium falciparum in vitro. Am J Trop Med Hyg 30: 531-7.
131. Troca-Marín JA, Alves-Sampaio A, Montesinos ML,. 2011. An increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome. J Neurosci 31: 9445-55.
132. Tsang CM, Lau EP, Di K, et al,. 2009. Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells. Int J Mol Med 24: 131-8.
133. Ueda M, Hayashibara K, Ashida H,. 2013. Propolis extract promotes translocation of glucose transporter 4 and glucose uptake through both PI3K- and AMPK-dependent pathways in skeletal muscle. Biofactors. In press.
134. Valeriote FA, Corbett TH, Grieco PA, et al,. 1998. Anticancer activity of glaucarubinone analogues. Oncol Res 10: 201-8.
135. Vergara, M., Smith-Wheelock, M., Harper, J., et al,. 2004. Hormone-treated snell dwarf mice regain fertility but remain long lived and resistant. J Gerontol A Biol Sci Med Sci 59: 1244-50.
136. Viollet B, Andreelli F,. 2011. AMP-activated protein kinase and metabolic control. Handb Exp Pharmacol (203): 303-30.
137. Waite KA, Sinden MR, Eng C,. 2005. Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet 14: 1457-63.
138. Wan Y, Wallinder C, Plouffe B, et al,. 2004. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. J Med Chem 47: 5995-6008.
139. Wang Z, Jin H, Xu R, et al,. 2009. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med 41: 717-27.
140. Westfall R,. 1993. In: The life of Isaac Newton. Cambridge University Press: Cambridge.
141. Wiegant FA, Surinova S, Ytsma E, et al,. 2009. Plant adaptogens increase lifespan and stress resistance in C. elegans. Biogerontology 10: 27-42.
142. Wilson MA, Shukitt-Hale B, Kalt W, et al,. 2006. Blueberry polyphenols increase lifespan and thermotolerance in C. elegans. Aging Cell 5: 59-68.
143. Wu R, Abramson AL, Symons MH,. 2010. Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1-mediated COX-2 expression. Int J Cancer 127: 2230-7.
144. Xu JW, Ikeda K, Kobayakawa A,. et al. 2005a. Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells. Life Sci 76: 2861-72.
145. Xu Y, Ku BS, Yao HY, et al,. 2005b. Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82: 200-6.
146. Yanase S, Luo Y, Maruta H,. 2013. PAK1-deficiency/down-regulation Reduces Brood Size, Activates HSP16.2 Gene and Extends Lifespan in C. elegans. Drug Dev Ther 7: 29-35.
147. Yazawa S, Suetome N, Okamoto K,. et al. 1989. Content of capsiaicinoids and capsaicinoid-like substances in fruit of pepper (Capsicum annum L.) hybrids made with "CH-19 Sweet as a parent. J Jpn Soc Hortic Sci 58: 601-7.
148. Zang M, Xu S, Maitland-Toolan KA,. et al. 2006. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55: 2180-91.