Share This Article:

Phenylacetylglutaminate and Phenylacetate in Combination Upregulate VDUP1, Cause Cell Cycle Blockade and Apoptosis in U87 Glioblastoma Cells

Abstract Full-Text HTML XML Download Download as PDF (Size:1007KB) PP. 192-200
DOI: 10.4236/jct.2012.33028    3,958 Downloads   6,988 Views   Citations

ABSTRACT

Phenylacetylglutaminate (PG) and Phenylacetate (PN) are metabolites of Phenylbutyrate (PB) and are constituents of antineoplaston AS2-1. These are sodium salts of amino acid derivative and carboxylic acid that inhibit the growth of neoplastic cells without growth inhibitory effect in normal cells. The aim of this study was to identify molecular pathways involved in the anti-proliferative effect of antineoplastons. Using a total human genome microarray we have found that 1) Vitamin D3 upregulated protein (VDUP1) is significantly upregulated in response to PG and PN in the U87 glioblastoma cells; 2) Isobologram analysis shows that PG and PN act in an additive or synergistic manner to effectively suppress proliferation of U87 cells; 3) PG and PN cause cell cycle arrest, changes in expression of several cell cycle genes and suppress expression and activity of the G2/M checkpoint kinase, CHK1. The multiple cellular targets possibly make these compounds effective anti-proliferative agents. We propose that PG and PN in combination target important cellular pathways and upregulate VDUP1 leading to detachment-induced apoptosis in cancer cells.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

S. S. Patil, S. R. Burzynski, E. Mrowczynski, K. Grela and S. V. Chittur, "Phenylacetylglutaminate and Phenylacetate in Combination Upregulate VDUP1, Cause Cell Cycle Blockade and Apoptosis in U87 Glioblastoma Cells," Journal of Cancer Therapy, Vol. 3 No. 3, 2012, pp. 192-200. doi: 10.4236/jct.2012.33028.

References

[1] S. C. Piscitelli, A. Thibault, W. D. Figg, A. Tompkins, D. Headlee, R. Lieberman, D. Samid and C. E. Myers, “Disposition of Phenylbutyrate and Its Metabolites, Phenylacetate and Phenylacetylglutamine,” Journal of Clinical Pharmacology , Vol. 35, 1995, pp. 368-373.
[2] S. R. Burzynski, “Treatments for Astrocytic Tumors in Children: Current and Emerging Strategies,” Paediatr Drugs, Vol. 8, No. 3, 2006, pp. 67-178.
[3] S. R. Burzynski, “Recent Clinical Trials in Diffuse Intrinsic Brainstem Glioma,” Cancer Therapy, Vol. 5, No. 5, 2007, pp. 379-390.
[4] X. Li, S. Parikh, Q. Shu, H. Jung, C. Chow, L. Perlaky, et al., “Phenylbutyrate and Phenylacetate Induce Differentiation and Inhibit Proliferation of Human Medulloblastoma Cells,” Clinical Cancer Research, Vol. 10, 2004, pp. 1150-1159. doi:10.1158/1078-0432.CCR-0747-3
[5] T. Iannitti and B. Palmieri, “Clinical and Experimental Applications of Sodium Phenylbutyrate,” Drugs in Research and Development, Vol. 11, No. 3, 2011, pp. 227-249.
[6] D. Samid, W. R. Hudgins, S. Shack, L. Liu, P. Prasanna and C. E. Myers, “Phenylacetate and Phenylbutyrate as Novel, Nontoxic Differentiation Inducers,” Advances in Experimental Medical Biology, Vol. 400, 1997, pp. 501-505.
[7] D. Samid, Z. Ram and W. R. Hudgins, et al., “Selective Activity of Phenylacetate against Malignant Gliomas Resemblance to Fetal Brain Damage in Phenylketonuria,” Cancer Research, Vol. 54, No. 4, 1994, pp. 891-895.
[8] W. R. Hudgins, S. Shack, C. E. Myers and D. Samid, “Cytostatic Activity of Phenylacetate and Derivatives against Tumor Cells; Correlation with Lipophilicity and Inhibition of Protein Prenylation,” Biochemical Pharmacology, Vol. 50, No. 8, 1995, pp. 1273-1279. doi:10.1016/0006-2952(95)02013-3
[9] A. Thibault, D. Samid and M. R. Cooper, “Phase I Study of Phenylacetate Administered Twice Daily to Patients with Cancer,” Cancer, Vol. 75, No. 12, 1995, pp. 2932-2938. doi:10.1002/1097-0142(19950615)75:12<2932::AID-CNCR2820751221>3.0.CO;2-P
[10] M. Sandler, C. R. Ruthven, B. L. Goodwin, A. Lees and G. M. Stern, “Phenylacetic Acid in Human Body Fluids: High Correlation between Plasma and Cerebrospinal Fluid Concentration Values,” Journal of Neurological Neurosurgery and Psychiatry, Vol. 45, No. 4, 1982, pp. 366-368. doi:10.1136/jnnp.45.4.366
[11] S. W. Brusilow, “Phenylacetylglutamine May Replace Urea as a Vehicle for Waste Nitrogen Excretion,” Pediatric Research, Vol. 29, No. 2, 1991, pp. 147-150. doi:10.1203/00006450-199102000-00009
[12] T. Fujii, A. M. Nakamura, G. Yokoyama, M. Yamaguchi, K. Tayama, K. Miwa, et al., “Arrest by Pkc Alpha and MAPK Pathway in SKBR-3 Breast Cancer Cells,” Oncology Reports, Vol. 14, No. 2, pp. 489-494.
[13] H. Tsuda, A. Iemura, M. Sata, M. Uchida, K. Yamana and H. Hara, “Inhibitory Effect of Antineoplaston A10 and AS2-1 on Human Hepatocellular Carcinoma,” Kurume Medical Journal, Vol. 43, No. 2, 1996, pp. 137-147. doi:10.2739/kurumemedj.43.137
[14] X.-J. Qu, S.-X. Cui, Z.-G. Tian, X. Li, M.-H. Chen, W.-F. Xu, et al., “Induction of Apoptosis in Human Hepatocellular Carcinoma Cells by Synthetic Antineoplaston A10,” Anticancer Research, Vol. 27, No. 4B, 2007, pp. 2427-2431.
[15] S. Loewe and M. Die, “Versuch Einer Allgemeinen Pharmakologie der Arzneikombinationen,” Journal of Molecular Medicine, Vol. 6, No. 23, 1927, pp. 1077-1085. doi:10.1007/BF01890305
[16] S. Loewe, “Problems on the Practice of the Quantitative Evaluation of Drug Combinations,” Arzneimittelforschung, Vol. 11, 1961, pp. 899-902.
[17] R. J. Tallarida, “Drug synergism: Its Detection and Applications,” Journal of Pharmacological Experimental Therapy, Vol. 298, No. 3, 2001, pp. 865-872.
[18] K. Seifert and S. L. Croft, “In Vitro and in Vivo Interactions between Miltefosine and Other Antileishmanial Drugs,” Antimicrobial Agents in Chemotherapy, Vol. 50, No. 1, 2006, pp. 73-79. doi:10.1128/AAC.50.1.73-79.2006
[19] A. Nishiyama, M. Matsui, S. Iwata, K. Hirota, H. Masutani and H. Nakamura, “Identification of Thioredoxin-Binding Protein-2/Vitamin D(3) Upregulated Protein 1 as a Negative Regulator of Thioredoxin Function and Expression,” Journal of Biological Chemistry, Vol. 274, No. 31, 1999, pp. 21645-21650. doi:10.1074/jbc.274.31.21645
[20] M. Saitoh, H. Nishitoh, M. Fujii, K. Takeda, K. Tobiume, Y. Sawada, et al., “Mammalian Thioredoxin Is a Direct Inhibitor of Apoptosis Signal-Regulating Kinase (ASK) 1,” The EMBO Journal, Vol. 17, No. 9, 1998, pp. 2596-2606. doi:10.1093/emboj/17.9.2596
[21] P. A. Marks, “Thioredoxin in Cancer-Role of Histone Deacetylase Inhibitors,” Seminars in Cancer Biology, Vol. 16, No. 6, 2006, pp. 436-443. doi:10.1016/j.semcancer.2006.09.005
[22] Y. Hirose, M. S. Berger and R. O. Pieper, “Abrogation of the Chk1-Mediated G2 Checkpoint Pathway Potentiates Temozolomide-Induced Toxicity in a P53-Independent Manner in Human Glioblastoma Cells,” Cancer Research, Vol. 61, No. 15, 2001, pp. 5843-5849.
[23] R. G. Shao, C. X. Cao and Y. Pommier, “Abrogation of Chk1-Mediated S/G2 Checkpoint by UCN-01 Enhances Ara-C-Induced Cytotoxicity in Human Colon Cancer Cells,” Acta Pharmacologica Sinica, Vol. 25, No. 6, 2004, pp. 756-762.
[24] B. Furnari, N. Rhind and P. Russell, “Cdc25 Mitotic Inducer Targeted by Chk1 DNA Damage Checkpoint Kinase,” Science, Vol. 277, No. 5331, 1997, pp. 1495-1497. doi:10.1126/science.277.5331.1495
[25] M. Jung, “Inhibitors of Histone Deacetylase as New Anti-cancer Agents,” Current Medicinal Chemistry, Vol. 8, No. 12, 2001, pp. 1505-1511.
[26] S. H. Han, J. H. Jeon, H. R. Ju, et al. “VDUP1 Upregulated by TGF-Beta1 and 1,25-Dihydorxyvitamin D3 Inhibits Tumor Cell Growth by Blocking Cell-Cycle Progression,” Oncogene, Vol. 22, No. 26, 2003, pp. 4035-4046. doi:10.1038/sj.onc.1206610
[27] A. P. Gilmore, “Anoikis,” Cell Death and Differentiation, Vol. 12, No. 52, 2005, pp. 1473-1477. doi:10.1038/sj.cdd.4401723
[28] A. J. Valentijn, N. Zouq and A. P. Gilmore, “Anoikis,” Biochemical Society Transactions, Vol. 32, No. 3, 2004, pp. 421-425. doi:10.1042/BST0320421
[29] B. B. Zhou, H. J. Anderson and M. Roberge, “Targeting DNA Checkpoint Kinases in Cancer Therapy,” Cancer Biology and Therapy, Vol. 2, No. 4, 2003, pp. 16-22.
[30] Y. Sanchez, C. Wong, R. S. Thoma, R. Richman, Z. Wu, S. Elledge, et al., “Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25,” Science, Vol. 277, No. 5331, 1997, pp. 1497-1501. doi:10.1126/science.277.5331.1497
[31] Y. Sanchez, J. Bachant, H. Wang, F. Hu, D. Liu, M. Tetzlaff, et al., “Control of the DNA Damage Checkpoint by Chk1 and Rad53 Protein Kinases through Distinct Mechanisms,” Science, Vol. 286, No. 5442, 1999, pp. 1166-1171. doi:10.1126/science.286.5442.1166
[32] V. L. Gabai, C. O’Callaghan-Sunol, L. Meng, M. Y. Sherman and J. Yaglom, “Triggering Senescence Programs Suppresses Chk1 Kinase and Sensitizes Cells to Genotoxic Stresses,” Cancer Research, Vol. 68, No. 6, 2008, pp. 1834-1842. doi:10.1158/0008-5472.CAN-07-5656
[33] Y. Tang, W. Liu, J. Zhou, Q. Gao and J. Wu, “Apoptotic Sensitivity to Irradiation Increased after Transfection of Chk1 Antisense Chain to HL-60 Cell Line,” Journal of Huazhong University of Science and Technology Medical Science, Vol. 25, No. 5, 2005, pp. 513-515. doi:10.1007/BF02896003

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.