Can Plants’ Ability for DNA Repair and Stress Defense be Used against Patients’ Circulating Tumor Cells?
PDF

Keywords

Tp53
Tp21
Bax/Bcl2
MAP kinase
VEGF
CTC
circulating tumor cell
fermented soy
MDR protein
estrogen receptor beta
NF-KB, RT-PCR technique
human breast cancer cell line BT -474
ovarian cancer
breast cancer
prostate cancer

How to Cite

C.D. Volko, & U.D. Rohr. (2015). Can Plants’ Ability for DNA Repair and Stress Defense be Used against Patients’ Circulating Tumor Cells?. Journal of Pharmacy and Nutrition Sciences, 5(3), 157–178. https://doi.org/10.6000/1927-5951.2015.05.03.1

Abstract

Introduction: It was suggested that specific plants may reduce cancer's resistance to chemotherapy. Resistance inhibits apoptosis, as well as other fundamental anti-cancer protective mechanisms. Soy bean has been found to reduce cellular stress and repair DNA damage caused by drought or parasites, and can transfer this defense mechanism to other plant species as well. The aim of this study is therefore to conduct a systematic comparison of the effect of soy bean formulation (FSWW08) on gene expression in in vitro human breast cancer cell line, and in in vivo in blood circulating tumor cells (CTC), after oral consumption of FSWW08 by patients suffering from breast-, ovarian-, and prostate cancer.

Method: In vitro gene expressions studies were conducted with the human breast cancer cell line BT-474 that was exposed to doxorubicin or FSWW08, either alone or in combination. Ovarian-, prostate-, and breast cancer patients received FSWW08 for 30 days. CTC were extracted from their blood according to an established protocol. Gene expression evaluations were conducted before and after treatment.

Results: In vitro, the multi-drug resistance (MDR) protein was reduced by FSWW08, but was increased by doxorubicin. The combination of FSWW08 and doxorubicin, however, showed a protective effect against the increase of MDR in physiologic concentrations, increased, however, also in high experimental concentrations of both agents. The expression of several cancer-related protective genes, such as tumor suppressor factors p21, p38 and p53, was improved by FSWW08 in vitro and in vivo, which helped cell differentiation and new tissue formation. Additionally, the BAX/Bcl2 ratio was improved, in vitro, as well as gene expression of estrogen receptor beta, NF-κB, MAP kinase, c-JUN, and matrix metalloproteinase 9, together with an increase of VEGF expression in vivo in CTC.

Conclusion: It was demonstrated that FSWW08 improved the gene functions related to DNA repair and stress in human blood CTC and resistance marker, in vitro, when applied in combination with doxorubicin. As such, larger in vitro and in vivo clinical studies that investigate single botanical compounds from other plants, are warranted.

https://doi.org/10.6000/1927-5951.2015.05.03.1
PDF

References

Somani SM, JA Romano Jr, editors. Chemical Warfare Agents: Toxicity at Low Levels. Boca Raton, FL: CRC Press, 2001.

Waring MJ. DNA Modification and Cancer. Annual Review of Biochemistry 1981; 50: 159-192. http://dx.doi.org/10.1146/annurev.bi.50.070181.001111

Perez-Tomas R. Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment. Current Medicinal Chemistry 2006; 13: 1859-1876. http://dx.doi.org/10.2174/092986706777585077

Molnár J, Engi H, Hohmann J, Molnár P, Deli J, Wesolowska O, Michalak K, Wang Q. Reversal of multidrug resistance by natural substances from plants. Curr Top Med Chem 2010; 10: 1757-68. http://dx.doi.org/10.2174/156802610792928103

Wicha M. Cancer Stem Cells: An Old Idea-A Paradigm Shift. Cancer Res 2006; 66: 1883. http://dx.doi.org/10.1158/0008-5472.CAN-05-3153

Visvader JE, Lindeman GJ. Cancer Stem Cells: Current Status and Evolving Complexities. Cell Stem Cell 2012; 10: 717-728. http://dx.doi.org/10.1016/j.stem.2012.05.007

Sethi S, Li Y, Sarkar FH. Regulating miRNA by natural agents as a new strategy for cancer treatment. Curr Drug Targets 2013; 14: 1167-74. http://dx.doi.org/10.2174/13894501113149990189

Markstein M, Dettorre S, Cho J, Neumüller RA, Craig-Müller S, Perrimon N. Systematic screen of chemotherapeutics in Drosophila stem cell tumors. PNAS 2014; 14: 4530-5. http://dx.doi.org/10.1073/pnas.1401160111

Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S, Soroceanu L. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death and Disease 2015; 6. http://dx.doi.org/10.1038/cddis.2014.566

Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol 2015; 10: 425-48. http://dx.doi.org/10.1146/annurev-pathol-012414-040424

(a) Biddlestone J, Bandarra D, Rocha S. The role of hypoxia in inflammatory disease (Review). Int J Mol Med 2015. doi: 10.3892/ijmm.2015.2079 (b) Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski JM, Galindo Ramirez F, Rizzuto R, Di Virgilio F, Zito E, Pandolfi PP, Wieckowski MR, Mammano F, Del Sal G, Pinton P. p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc Natl Acad Sci USA 2015. pii: 201410723.

von Stechow L, Typas D, Carreras Puigvert J, Oort L, Siddappa R, Pines A, Vrieling H, van de Water B, Mullenders LH, Danen EH. The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Mol Cell Biol 2015. pii: MCB.01152-14.

Richardson C, Yan S, Vestal CG. Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells. Int J Mol Sci 2015; 16(2): 2366-2385. Review.

Paul S, Amundson SA. Differential Effect of Active Smoking on Gene Expression in Male and Female Smokers. J Carcinog Mutagen 2014; 5: pii 1000198.

Wong EY, Wong SC, Chan CM, Lam EK, Ho LY, Lau CP, Au TC, Chan AK, Tsang CM, Tsao SW, Lui VW, Chan AT. TP53-induced glycolysis and apoptosis regulator promotes proliferation and invasiveness of nasopharyngeal carcinoma cells. Oncol Lett 2015; 9(2): 569-574.

Gu Y, Li P, Peng F, Zhang M, Zhang Y, Liang H, Zhao W, Qi L, Wang H, Wang C, Guo Z. Autophagy-related prognostic signature for breast cancer. Mol Carcinog 2015. http://dx.doi.org/10.1002/mc.22278

Rapisarda V, Loreto C, Ledda C, Musumeci G, Bracci M, Santarelli L, Renis M, Ferrante M, Cardile V. Cytotoxicity, oxidative stress and genotoxicity induced by glass fibers on human alveolar epithelial cell line A549. Toxicol In Vitro 2015. pii: S0887-2333(14)00250-1. http://dx.doi.org/10.1016/j.tiv.2014.12.010

Vaubourgeix J, Lin G, Dhar N, Chenouard N, Jiang X, Botella H, Lupoli T, Mariani O, Yang G, Ouerfelli O, Unser M, Schnappinger D, McKinney J, Nathan C. Stressed Mycobacteria Use the Chaperone ClpB to Sequester Irreversibly Oxidized Proteins Asymmetrically Within and Between Cells.Cell Host Microbe 2015. pii: S1931-3128(14)00462-4. http://dx.doi.org/10.1016/j.chom.2014.12.008

Ganai AA, Khan AA, Malik ZA, Farooqi H. Genistein modulates the expression of NF-?B and MAPK (p-38 and ERK1/2), thereby attenuating d-Galactosamine induced fulminant hepatic failure in Wistar rats. Toxicol Appl Pharmacol 2015. pii: S0041-008X(15)00022-8. http://dx.doi.org/10.1016/j.taap.2015.01.012

Fulda S, Kögel D. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene 2015. http://dx.doi.org/10.1038/onc.2014.45

Shaukat Z, Liu D, Hussain R, Khan M, Gregory SL. The Role of JNK Signalling in Responses to Oxidative DNA Damage. Curr Drug Targets 2015. [Epub ahead of print

Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem 2011; 9: 799-806.

Fehm T, Hoffmann O, Aktas B, Becker S, Solomayer EF, Wallwiener D, Kimmig R, Kasimir-Bauer S. Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Research 2009; 11: R59. http://dx.doi.org/10.1186/bcr2349

Rohr UD, Gocan AG, Bachg D, Schindler AE. The effect of fermented soy (FSWW08) on blood hematology and cachexia in cancer patients. Horm Mol Biol Clin Invest 2010; 3: 391-409.

Atkinson NJ, Urwin PE. The interaction of plant biotic and abiotic stresses: from genes to the ?eld. Journal of Experimental Botany 2012; 17: 1-21. http://dx.doi.org/10.1093/jxb/ers100

West CE, Waterworth WM, Sunderland PA, Bray CM. Arabidopsis DNA double-strand break repair pathways. Biochem Soc Trans 2004; 32: 964-966. http://dx.doi.org/10.1042/BST0320964

Kozak J, West CE, White C, da Costa-Nunes JA, Angelis KJ. Rapid repair of DNA double strand breaks in Arabidopsis thaliana is dependent on proteins involved in chromosome structure maintenance. DNA Repair (Amst) 2014; 8: 413-419. http://dx.doi.org/10.1016/j.dnarep.2008.11.012

Roy S, Roy CS, Singh SK, Das KP. AtPol? a homolog of mammalian DNA polymerase ? in Arabidopsis thaliana, is involved in there pair of UV-B induced DNA damage through the dark repair pathway. Plant Cell Physiol 2011; 52: 448-467. http://dx.doi.org/10.1093/pcp/pcr002

Roy S. Maintenance of genome stability in plants: repairing DNA doublw strand breaks and chromatin structure stability. Frontiers in Plant Science 2014. http://dx.doi.org/10.3389/fpls.2014.00487

Rodriguez MCS, Petersen M, Mundy J. Mitogen-activated protein kinase signaling in plants. Annual Review of Plant Biology 2010; 61: 621-649. http://dx.doi.org/10.1146/annurev-arplant-042809-112252

Zhang T, Liu Y, Yang T, Zhang L, Xu S, Xue L, An L. Diverse signals converge at MAPK cascades in plant. Plant Physiology and Biochemistry 2006; 44: 274-283. http://dx.doi.org/10.1016/j.plaphy.2006.06.004

Yoshiyama KO, Sakaguchi K, Kimura S. DNA damage response in plants: conserved and variable response compared to animals. Biology (Basel) 2014; 2: 1338-1356. http://dx.doi.org/10.3390/biology2041338

Biros E1, Kohút A, Biros I, Kalina I, Bogyiová E, Stubna J. A link between the p53 germ line polymorphisms and white blood cells apoptosis in lung cancer patients. Lung Cancer 2002; 35: 231-5. http://dx.doi.org/10.1016/S0169-5002(01)00446-9

Schönrock N, Exner V, Probst A, Gruissem W, Hennig L. Functional genomic analysis of CAF-1 mutants in Arabidopsis thaliana. J Biol Chem 2006; 281: 9560-9568. http://dx.doi.org/10.1074/jbc.M513426200

Ramirez-Parra E, Gutierrez C. E2F regulates FASCIATA1, a chromatin assembly gene whose loss switches on the endocycle and activates gene expression by changing the epigenetic status. Plant Physiol 2007; 144: 105-120. http://dx.doi.org/10.1104/pp.106.094979

Kulcheski FR, de Oliveira LFV, Molina LG, et al. Identi?cation of novel soybean microRNAs involved in abiotic and biotic stresses. BMC Genomics 2011; 12: 307. http://dx.doi.org/10.1186/1471-2164-12-307

Rotino GL, Rossoni M, Spinardi A, Bracale M. 2007. Evaluation of transgenic tomato plants ectopically expressing the rice Osmyb4 gene. Plant Science 2011; 173: 231-239.

Hu WS, Lin YM, Ho TJ, Chen RJ, Li YH, Tsai FJ, Tsai CH, Day CH, Chen TS, Huang CY. Genistein suppresses the isoproterenol-treated H9c2 cardiomyoblast cell apoptosis associated with P-38, Erk1/2, JNK, and NF?B signaling protein activation. Am J Chin Med 2013; 41: 1125-36. http://dx.doi.org/10.1142/S0192415X13500766

Rohr UD, WW Li, H Ziqiang, Wainright, AE Schindler. The effect of fermented soy (FSWW08) on blood hematology and cachexia in cancer patients. Hormone Molecular Biology and Clinical Investigation 2012; 12: 407-418. http://dx.doi.org/10.1515/hmbci-2012-0028

Gocan AG. D Bachg, AE Schindler, UD Rohr. Managing immunity in resistant cancer patients correlates to survival: results and discussion of a pilot study. Horm Mol Biol Clin Invest 2011; 8: 455-469.

Rostagno P, Moll JL, Bisconte JC, Caldani C. Detection of rare circulating breast cancer cells by filtration cytometry and identification by DNA content: sensitivity in an experimental model. Anticancer Res 1997; 17: 2481-5.

Hardingham JE, Kotasek D, Farmer B, Butler RN, Mi JX, Sage RE, Dobrovic A. Immunobead-PCR: a technique for the detection of circulating tumor cells using immunomagnetic beads and the polymerase chain reaction. Cancer Res 1993; 53: 3455-8.

Ferreira E, Cronjé MJ. Selection of suitable reference genes for quantitative real-time PCR in apoptosis-induced MCF-7 breast cancer cells. Mol Biotechnol 2012; 50: 121-126. http://dx.doi.org/10.1007/s12033-011-9425-3

Klein A, He X, Roche M, Mallett A, Duska L, Supko JG, Seiden MV. Prolonged stabilization of platinum-resistant ovarian cancer in a single patient consuming a fermented soy therapy. Gynecol Oncol 2006; 100: 205-9. http://dx.doi.org/10.1016/j.ygyno.2005.08.006

Alwan A, MacLean DR, Riley LM. Monitoring and surveillance of chronic non-communicable diseases: progress and capacity in high-burden countries. The Lancet 2010; 376: 1861-1868. http://dx.doi.org/10.1016/S0140-6736(10)61853-3

Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: Oncogene and non-oncogene addiction. Cell 2009; 136(5): 823-837. http://dx.doi.org/10.1016/j.cell.2009.02.024

Aggarwal BB, Danda D, Gupta S, Gehlot P. Models for prevention and treatment of cancer: Problems vs promises. Biochem Pharmacol 2009; 78: 1083-1094. http://dx.doi.org/10.1016/j.bcp.2009.05.027

Noolvi MN. Natural sources as potential anti-cancer agents: A review. International Journal of Phytomedicine 2011; 3: 09-26.

Gocan AG, Bachg D, Schindler AE, Rohr UD. Balancing steroidal hormone cascade in treatment-resistant veteran soldiers with PTSD using a fermented soy product (FSWW08): a pilot study. Horm Mol Biol Clin Invest 2012; 10: 301-314.

Bachen, EA, Manuck SB, Cohen S, Muldoon MF, Raible R, Herbert TB, Rabin BS. Adrenergic Blockade Ameliorates Cellular Immune Responses to Mental Stress in Humans. Psychosomatic Medicine 1995; 57: 366-372. http://dx.doi.org/10.1097/00006842-199507000-00008

Zhang Z, Wang CZ, Du GJ, Qi Calway LW. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol 2013; 43: 289-96.

Bao X, Fen Y, Mian Z, Xue Y, Zhi Z. Effect of genistein on the TLR and MAPK transduction cascades in lipopolysaccharide-stimulated macrophages.

Sandner A, Illert J, Koitzsch S, Unverzagt S, Schön I. Reflux induces DNA strand breaks and expression changes of MMP1+9+14 in a human miniorgan culture model. Exp Cell Res 2013; 319: 2905-15. http://dx.doi.org/10.1016/j.yexcr.2013.09.004

Magee PJ, Allsopp P, Samaletdin A, Rowland IR. Daidzein, R-(+)equol and S-(-)equol inhibit the invasion of MDA-MB-231 breast cancer cells potentially via the down-regulation of matrix metalloproteinase-2. Eur J Nutr 2014; 53: 345-50. http://dx.doi.org/10.1007/s00394-013-0520-z

Zheng W, Zhang Y, Ma D, Shi Y, Liu C, Wang P. (±)Equol inhibits invasion in prostate cancer DU145 cells possibly via down-regulation of matrix metalloproteinase-9, matrix metalloproteinase-2 and urokinase-type plasminogen activaton by antioxidant activity. J Clin Biochem Nutr 2012; 51: 61-7. http://dx.doi.org/10.3164/jcbn.11-54

Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009; 9: 400-414. http://dx.doi.org/10.1038/nrc2657

Levine AJ. The P53 tumor suppressor gene. Nature 1991; 351: 453. http://dx.doi.org/10.1038/351453a0

Tanner M, Jarvinen P, Isola J. Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res 2001; 61: 5345-8.

Piao Y, Liang J, Holmes L, Henry V, Sulman E, de Groot JF. Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition. Clin Cancer Res 2013; 19: 4392-403. http://dx.doi.org/10.1158/1078-0432.CCR-12-1557

Zhao D, Pan C, Sun J, Gilbert C, Drews-Elger K, Azzam DJ, Picon-Ruiz M, Kim M, Ullmer W, El-Ashry D, Creighton CJ, Slingerland JM. VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene 2014. http://dx.doi.org/10.1038/onc.2014.257

Chedraui P, Solis EJ, Bocci G, Gopal S, Russo E, Escobar GS, Hidalgo L, Pérez-López FR, Genazzani AR, Mannella P, Simoncini T. Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. J Matern Fetal Neonatal Med 2013; 26: 226-32. http://dx.doi.org/10.3109/14767058.2012.733760

Goel HL, Mercurio AM. VEGF targets the tumour cell. Nature Reviews Cancer 2013; 13: 871-882. http://dx.doi.org/10.1038/nrc3627

Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang J, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SPAnti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci 2011; 108: 3749-5. http://dx.doi.org/10.1073/pnas.1014480108

Krajewski S. et al. Prognostic significance of apoptosis regul-ators in breast cancer. Endocr Relat Cancer 1999; 6: 29-40. http://dx.doi.org/10.1677/erc.0.0060029

Ikeguchi MS. et al. Quantitative analysis of expression levels of BAX, Bcl 2 and survivin in cancer cells during cisplatin treatment. Oncol Rep 2002; 9: 1121-6. http://dx.doi.org/10.3892/or.9.5.1121

Pennell RI, Lamb C. Plant Cell 1997; 9: 1157-1168. http://dx.doi.org/10.1105/tpc.9.7.1157

Greenberg, JT. Plant Mol Biol 1997; 48: 525-545.

Heath MC, Eur. J Plant Pathol 1998; 104: 117-124. http://dx.doi.org/10.1023/A:1008645520976

Gilchrist DG. Annu. Rev. Phytopathol 1998; 36: 393-414. http://dx.doi.org/10.1146/annurev.phyto.36.1.393

Lacomme C, Santa Cruz S. Bax-induced cell death in tobacco is similar to the hypersensitive response. Proc Natl Acad Sci 1999; 96: 7956-7961. http://dx.doi.org/10.1073/pnas.96.14.7956

Goodman RN, Novacky AJ. The Hypersensitive Reaction in Plants to Pathogens. A Resistance Phenomenon 1994 APS Press, St. Paul, MN.

Kromer G. Nat Med 1997; 3: 614-620. http://dx.doi.org/10.1038/nm0697-614

Oltvai ZN, Milliman CL, Korsmeyer SJ. Cell 1993; 74: 609-619. http://dx.doi.org/10.1016/0092-8674(93)90509-O

Zha H, Aime-Sempe C, Sato T, Reed JC. J Biol Chem 1997; 271: 7440-7444.

Simonen M, Keller H, Heim J. Eur J Biochem 1997; 249: 85-91. http://dx.doi.org/10.1111/j.1432-1033.1997.t01-1-00085.x

Napetschnig J, Wu H. Molecular Basis of NF-?B Signaling. Biophysics 2013; 42: 443-468. http://dx.doi.org/10.1146/annurev-biophys-083012-130338

Golan-Goldhirsh A, Gopas J. Plant derived inhibitors of NF-?B. Phytochemistry Reviews 2014; 13: 107-121. http://dx.doi.org/10.1007/s11101-013-9293-5

Rouleau M, Marsolais F, Richard M, Nicolle L, Voigt B, Adam G Varin L. Inactivation of Brassinosteroid Biological Activity by a Salicylate-inducible Steroid Sulfotransferase from Brassica napus. The Journal of Biological Chemistry 1999; 274: 20925-20930. http://dx.doi.org/10.1074/jbc.274.30.20925

Thornton. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. PNAS 2001; 98: 5673-79.

Holmes DHI, Zachar I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biology 2005; 6: 209. http://dx.doi.org/10.1186/gb-2005-6-2-209

Negi S, Kharshiing EV, Sharma R. NO way! Is nitric oxide level in tomato regulated by a mammalian IKK/NF?B-like signaling pathway? Plant Signal Behav 2011; 6(7): 1049-1052. http://dx.doi.org/10.4161/psb.6.7.15633

Goslin K, Schindler AE, Rohr UD. Prolonged Stabilization of Amyotrophic Lateral Sclerosis (ALS) with a specially fermented Soy Product (FSWW08): Case Report and Discussion. Journal of Nutritional Therapeutics 2013; 2: 1.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright (c) 2015 C.D. Volko , U.D. Rohr