期刊论文详细信息
Journal of Experimental & Clinical Cancer Research
CELLFOOD™ induces apoptosis in human mesothelioma and colorectal cancer cells by modulating p53, c-myc and pAkt signaling pathways
Rossella Galati2  Franco Canestrari1  Serena Benedetti1  Serafina Battistelli1  Simona Catalani1  Raffaela Santoro2  Barbara Nuvoli2 
[1] Department of Biomolecular Sciences, Section of Clinical Biochemistry and Cellular Biology, University of Urbino “Carlo Bo”, Via Ubaldini 7, 61029 Urbino, PU, Italy;Molecular Medicine Area, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
关键词: Colorectal cancer;    Mesothelioma;    Nutraceutical;    CELLFOOD™ (CF);   
Others  :  804302
DOI  :  10.1186/1756-9966-33-24
 received in 2014-02-14, accepted in 2014-02-27,  发布年份 2014
PDF
【 摘 要 】

Background

CELLFOOD™ (CF) is a nutraceutical non-addictive, non-invasive, and completely non-toxic unique proprietary colloidal-ionic formula. Little is known about its effect on cancer cells in solid tumors. The aim of this study was to evaluate the effect that CF has on different cancer cell lines and the mechanism by which the nutraceutical works.

Methods

The effect of CF on HFF (normal fibroblasts), Met5A (mesothelium), MSTO-211H, NCI-2452, Ist-Mes1, MPP89, Ist-Mes2 (mesothelioma), M14 (melanoma), H1650, H1975 (lung cancer), SKRB3 (breast cancer), and HCT-116 (colorectal cancer) cell growth was tested by cell proliferation and clonogenic assay. Among all of them, MSTO-211 and HCT-116 were analyzed for cell cycle by flow cytometry and western blot.

Results

All human cancer lines were suppressed on cell growth upon 1:200 CF treatment for 24 and 48 hours. Death was not observed in HFF and Met5A cell lines. Cell cycle analysis showed an increased sub-G1 with reduction of G1 in MSTO-211 and a cell cycle arrest of in G1 in HCT116. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for both cell lines. Increased expression levels of p53, p21, and p27, downregulation of c-myc and Bcl-2, and inhibition of Akt activation were also found in CF-treated MSTO-211 and HCT-116 cells.

Conclusions

These findings ascertained an interaction between p53, c-myc, p21, p27, Bcl-2, PI3K/Akt pathway, and CF-induced apoptosis in MSTO-211H and HCT-116 cells, suggesting that CF acts as an important regulator of cell growth in human cancer cell lines. CF could be a useful nutraceutical intervention for prevention in colon cancer and mesothelioma.

【 授权许可】

   
2014 Nuvoli et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140708055937604.pdf 1279KB PDF download
Figure 5. 22KB Image download
Figure 4. 26KB Image download
Figure 3. 84KB Image download
Figure 2. 34KB Image download
Figure 1. 77KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】
  • [1]Benedetti S, Catalani S, Palma F, Canestrari F: The antioxidant protection of CELLFOOD against oxidative damage in vitro. Food Chem Toxicol 2011, 49:2292-2298.
  • [2]Nieddu ME, Menza L, Baldi F, Frediani B, Marcolongo R: Efficacy of Cellfood’s therapy (deutrosulfazyme) in fibromyalgia. Reumatismo 2007, 59:316-321.
  • [3]Catalani S, Carbonaro V, Palma F, Arshakyan M, Galati R, Nuvoli B, Battistelli S, Canestrari F, Benedetti S: Metabolism modifications and apoptosis induction after CellfoodTM administration to leukemia cell lines. J Exp Clin Cancer Res 2013, 32:63. BioMed Central Full Text
  • [4]Green DR, Evan GI: A matter of life and death. Cancer Cell 2002, 1:19-30.
  • [5]Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev 1999, 13:2905-2927.
  • [6]Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991, 51:6304-6311.
  • [7]Mansur CP: The regulation and function of the p53 tumor suppressor. Adv Dermatol 1997, 13:121-166.
  • [8]Sandor J, Ambrus T, Ember I: The function of the p53 gene suppressor in carcinogenesis. Orv Hetil 1995, 136:1875-1883.
  • [9]Schoneich C: Protein modification in aging: an update. Exp Gerontol 2006, 41:807-812.
  • [10]Liu D, Xu Y: p53, oxidative stress, and aging. Antioxid Redox Signal 2011, 15:1669-1678.
  • [11]Gottlieb TM, Oren M: p53 in growth control and neoplasia. Biochim Biophys Acta 1996, 1287:77-102.
  • [12]Levy N, Yonish-Rouach E, Oren M, Kimchi A: Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. Mol Cell Biol 1993, 13:7942-7952.
  • [13]Vennstrom B, Sheiness D, Zabielski J, Bishop JM: Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol 1982, 42:773-779.
  • [14]Pelengaris S, Khan M, Evan G: c-MYC: more than just a matter of life and death. Nat Rev Cancer 2002, 2:764-776.
  • [15]Vita M, Henriksson M: The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 2006, 16:318-330.
  • [16]Meyer N, Penn LZ: Reflecting on 25 years with MYC. Nat Rev Cancer 2008, 8:976-990.
  • [17]Amati B, Alevizopoulos K, Vlach J: Myc and the cell cycle. Front Biosci 1998, 3:D250-D268.
  • [18]Dang CV: c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999, 19:1-11.
  • [19]Eilers M: Control of cell proliferation by Myc family genes. Mol Cells 1999, 9:1-6.
  • [20]Jung P, Hermeking H: The c-MYC-AP4-p21 cascade. Cell Cycle 2009, 8:982-989.
  • [21]Gartel AL, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F, Tyner AL: Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci U S A 2001, 98:4510-4515.
  • [22]Müller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, Ansorge W, Huttner W, Eilers M: Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes. Oncogene 1997, 15:2561-2576.
  • [23]Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13:1501-1512.
  • [24]Strasser A, Harris AW, Bath ML, Cory S: Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 1990, 348:331-333.
  • [25]Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, Cox MC, Franchi A, Bruno A, Mazzone C, Panetta P, Suppo G, Masi M, Amadori S: Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 2003, 101:2125-2131.
  • [26]Minn AJ, Rudin CM, Boise LH, Thompson CB: Expression of bcl-xL can confer a multidrug resistance phenotype. Blood 1995, 86:1903-1910.
  • [27]Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, Igawa M: Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res 2006, 12:6116-6124.
  • [28]Li ZX, Ouyang KQ, Jiang X, Wang D, Hu Y: Curcumin induces apoptosis and inhibits growth of human Burkitt’s lymphoma in xenograft mouse model. Mol Cells 2009, 27:283-289.
  • [29]Leow PC, Tian Q, Ong ZY, Yang Z, Ee PL: Antitumor activity of natural compounds, curcumin and PKF118–310, as Wnt/beta-catenin antagonists against human osteosarcoma cells. Invest New Drugs 2010, 28:766-782.
  • [30]Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, Krishnan S: Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factorkappaB- regulated gene products. Clin Cancer Res 2008, 14:2128-2136.
  • [31]Hong WK, Sporn MB: Recent advances in chemoprevention of cancer. Science 1997, 278:1073-1077.
  • [32]Wattenberg LW: What are the critical attributes for cancer chemopreventive agents? Ann NY Acad Sci 1995, 768:73-81.
  • [33]Smith TJ, Hong J-Y, Wang Z-Y, Yang CS: How can carcinogenesis be inhibited? Ann NY Acad Sci 1995, 768:82-90.
  • [34]Sun SY, Hail N Jr, Lotan R: Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 2004, 96:662-672.
  • [35]Huang Y, Hu J, Zheng J, Li J, Wei T, Zheng Z, Chen Y: Down-regulation of the PI3K/Akt signaling pathway and induction of apoptosis in CA46 Burkitt lymphoma cells by baicalin. J Exp Clin Cancer Res 2012, 31:48. BioMed Central Full Text
  • [36]Krifa M, Alhosin M, Muller CD, Gies JP, Chekir-Ghedira L, Ghedira K, Mély Y, Bronner C, Mousli M: Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down-regulation. J Exp Clin Cancer Res 2013, 32:30. BioMed Central Full Text
  • [37]Saldanha SN, Tollefsbol TO: The role of nutraceuticals in chemoprevention and chemotherapy and their clinical outcomes. J Oncol 2012, 2012:192464.
  • [38]Warburg O: On respiratory impairment in cancer cells. Science 1956, 124:269-270.
  • [39]Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D: Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev 2003, 29:297-307.
  • [40]Harris AL: Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002, 2:38-47.
  • [41]Iorio EL: Hypoxia, free radicals and antioxidants. The “Deutrosulfazyme®” paradox. Hypoxia Med J 2006, 1:2-32.
  • [42]Ferrero E, Fulgenzi A, Belloni D, Foglieni C, Ferrero ME: Cellfood™ improves respiratory metabolism of endothelial cells and inhibits hypoxia-induced reactive oxygen species (ROS) generation. J Physiol Pharmacol 2011, 62:287-293.
  • [43]Robinson LA, Reilly RB: Localized pleural mesothelioma. The clinical spectrum. Chest 1994, 106:1611-1615.
  • [44]Broaddus VC: Asbestos, the mesothelial cell and malignancy: a matter of life or death. Am J Respir Cell Mol Biol 1997, 17:657-659.
  • [45]World Health Organization: Cancer Incidence in Five Continents. Lyon: The World Health Organization and The International Agency for Research on Cancer; 2002.
  • [46]Starzynska T, Bromley M, Ghosh A, Stern PL: Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 1992, 66:558-562.
  • [47]Altomare DA, Menges CW, Xu J, Pei J, Zhang L, Tadevosyan A, Neumann-Domer E, Liu Z, Carbone M, Chudoba I, Klein-Szanto AJ, Testa JR: Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLoS ONE 2011, 6(4):e18828.
  • [48]Boxer LM, Dang CV: Translocations involving c-myc and c-myc function. Oncogene 2001, 20:5595-5610.
  • [49]Adhikary S, Eilers M: Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 2005, 6:635-645.
  • [50]Ramael M, Van den Bossche J, Buysse C, Deblier I, Segers K, Van Marck E: Immunoreactivity for c-fos and c-myc protein with the monoclonal antibodies 14E10 and 6E10 in malignant mesothelioma and non-neoplastic mesothelium of the pleura. Histol Histopathol 1995, 10:639-643.
  • [51]Smith DR, Goh HS: Overexpression of the c-myc proto-oncogene in colorectal carcinoma is associated with a reduced mortality that is abrogated by point mutation of the p53 tumor suppressor gene. Clin Cancer Res 1996, 2:1049-1053.
  • [52]Marshall GM, Gherardi S, Xu N, Neiron Z, Trahair T, Scarlett CJ, Chang DK, Liu PY, Jankowski K, Iraci N, Haber M, Norris MD, Keating J, Sekyere E, Jonquieres G, Stossi F, Katzenellenbogen BS, Biankin AV, Perini G, Liu T: Transcriptional upregulation of histone deacetylase 2 promotes Myc-induced oncogenic effects. Oncogene 2010, 29:5957-5968.
  • [53]Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL: The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985, 318:533-538.
  • [54]Morgenbesser SD, DePinho RA: Use of transgenic mice to study myc family gene function in normal mammalian development and in cancer. Semin Cancer Biol 1994, 5:21-36.
  • [55]Nasi S, Ciarapica R, Jucker R, Rosati J, Soucek L: Making decisions through Myc. FEBS Lett 2001, 490:153-162.
  • [56]Oka N, Tanimoto S, Taue R, Nakatsuji H, Kishimoto T, Izaki H, Fukumori T, Takahashi M, Nishitani M, Kanayama HO: Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci 2006, 97:1093-1098.
  • [57]Dieterle A, Orth R, Daubrawa M, Grotemeier A, Alers S, Ullrich S, Lammers R, Wesselborg S, Stork B: The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Int J Cancer 2009, 125:932-941.
  • [58]Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y: Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 2005, 117:376-380.
  • [59]Kai K, D'Costa S, Sills RC, Kim J: Inhibition of the insulin-like growth factor 1 receptor pathway enhances the antitumor effect of cisplatin in human malignant mesothelioma cell lines. Cancer Lett 2009, 278:49-55.
  • [60]Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R, Moch H, Weder W: PTEN expression is a strong predictor of survival in mesothelioma patients. Eur J Cardiothorac Surg 2008, 33:502-506.
  • [61]Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE: Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000, 275:10761-10766.
  • [62]Manion MK, Hockenbery DM: Targeting BCL-2- related proteins in cancer therapy. Cancer Biol Ther 2003, 2:S105-S114.
  • [63]Li L, Haynes P, Bender JR: Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells. Proc Natl Acad Sci U S A 2003, 100:4807-4812.
  文献评价指标  
  下载次数:0次 浏览次数:9次