Issue
Urtica dioica inhibits cell growth and induces apoptosis by targeting Ornithine decarboxylase and Adenosine deaminase as key regulatory enzymes in adenosine and polyamines homeostasis in human breast cancer cell lines
Corresponding Author(s) : Haleh Akhavan-Niaki
Cellular and Molecular Biology,
Vol. 64 No. 3: Issue 3
Abstract
Breast cancer is a heterogeneous and multifactorial disease with variable disease progression risk, and treatment response. Urtica dioica is a traditional herb used as an adjuvant therapeutic agent in cancer. In the present study, we have evaluated the effects of the aqueous extract of Urtica dioica on Adenosine deaminase (ADA) and Ornithine decarboxylase (ODC1) gene expression in MCF-7, MDA-MB-231, two breast cancer cell lines being estrogen receptor positive and estrogen receptor negative, respectively. Cell lines were cultured in suitable media. After 24 h, different concentrations of the extract were added and after 72 h, ADA and ODC1 gene expression as well as BCL2 and BAX apoptotic genes were assessed by Taqman real time PCR assay. Cells viability was assessed by MTT assay, and apoptosis was also evaluated at cellular level. The intra and extracellular levels of ODC1 and ADA enzymes were evaluated by ELISA. Results showed differential expression of ADA and ODC1 genes in cancer cell lines. In MCF-7 cell line, the expression level of ADA was upregulated in a dose-dependent manner but its expression did not change in MDA-MB cell line. ODC1 expression was increased in both examined cell lines. Also, increased level of the apoptotic BAX/BCL-2 ratio was detected in MCF-7 cells. These results demonstrated that Urtica dioica induces apoptosis in breast cancer cells by influencing ODC1 and ADA genes expression, and estrogen receptors. The different responses observed with these cell lines could be due to the interaction of Urtica dioica as a phytoestrogen with the estrogen receptor.
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- Brown W, Ahnen D. The international health care burden of cancers of the gastrointestinal tract and liver. Cancer Res Front. 2014;1:1-9.
- Amini Navaie B, Kavoosian S, Fattahi S, Hajian-Tilaki K, Asouri M, Bishekolaie R, et al. Antioxidant and Cytotoxic Effect of Aqueous and Hydroalcoholic Extracts of the Achillea Millefolium L. on MCF-7 Breast Cancer Cell Line. International Biological and Biomedical Journal. 2015;1:119-25.
- Sharma G N, Dave R, Sanadya J, Sharma P, Sharma K K. Various types and management of breast cancer: an overview. J Adv Pharm Technol Res. 2010;1:109-26.
- Coates A S, Winer E P, Goldhirsch A, Gelber R D, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26:1533-46.
- Liao G S, Apaya M K, Shyur L F. Herbal medicine and acupuncture for breast cancer palliative care and adjuvant therapy. Evid Based Complement Alternat Med. 2013;2013:437948.
- Ma H, Carpenter C L, Sullivan-Halley J, Bernstein L. The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors--results of a prospective study. BMC Cancer. 2011;11:222.
- Fattahi S, Golpour M, Akhavan Niaki H. Urtica Dioica, An Emerauld in the Medical Kingdom. International Biological and Biomedical Journal. 2016;2:1-10.
- Asgarpanah J, Mohajerani R. Phytochemistry and pharmacologic properties of Urtica dioica L. Journal of Medicinal Plants Research. 2012;6:5714-9.
- Upton R. Stinging nettles leaf (Urtica dioica L.): Extraordinary vegetable medicine. Journal of Herbal Medicine. 2013;3:9-38.
- Fattahi S, Ardekani A M, Zabihi E, Abedian Z, Mostafazadeh A, Pourbagher R, et al. Antioxidant and apoptotic effects of an aqueous extract of Urtica dioica on the MCF-7 human breast cancer cell line. Asian Pac J Cancer Prev. 2013;14:5317-23.
- Tullo A, Mastropasqua G, Bourdon J C, Centonze P, Gostissa M, Costanzo A, et al. Adenosine deaminase, a key enzyme in DNA precursors control, is a new p73 target. Oncogene. 2003;22:8738-48.
- Apasov S G, Blackburn M R, Kellems R E, Smith P T, Sitkovsky M V. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest. 2001;108:131-41.
- Zhu Q, Jin L, Casero R A, Davidson N E, Huang Y. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells. Breast Cancer Res Treat. 2012;136:57-66.
- Nowotarski S L, Woster P M, Casero R A, Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013;15:e3.
- Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8-14.
- Gerner E W, Meyskens F L, Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004;4:781-92.
- Pandamooz S, Hadipour A, Akhavan-Niaki H, Pourghasem M, Abedian Z, Ardekani A M, et al. Short exposure to collagenase and coculture with mouse embryonic pancreas improve human dermal fibroblast culture. Biotechnol Appl Biochem. 2012;59:254-61.
- Fattahi S, Amirbozorgi G, Lotfi M, Amini Navaei B, Kavoosian S, Asouri M, et al. Development of a Universal Taqman Probe for mRNA Gene Expression Analysis. Iranian Journal of Science and Technology, Transactions A: Science. [journal article]. 2017:1-8.
- Fattahi S, Pilehchian Langroudi M, Samadani A A, Nikbakhsh N, Asouri M, Akhavan-Niaki H. Application of unique sequence index (USI) barcode to gene expression profiling in gastric adenocarcinoma. J Cell Commun Signal. 2017;11:97-104.
- Shukla S, Mehta A. Anticancer potential of medicinal plants and their phytochemicals: a review. Brazilian Journal of Botany. [journal article]. 2015;38:199-210.
- Keshavarz S, Ardekani M R S, Safavi M, Chahardouli B, Nadali F. In vitro cytotoxic effect of urtica dioica extracts on acute myelogenous leukemia cell line (kg-1). Archives of Medical Laboratory Sciences. 2016;2.
- í‡agıl F Z, Akal Z U, Alpsoy L. Cytotoxic and Apoptotic Effects of Urticadioica Agglutinin on AGS Cells. . Med chem. 2015;5:124-9.
- Ham J, Evans B A. An emerging role for adenosine and its receptors in bone homeostasis. Front Endocrinol (Lausanne). 2012;3:113.
- Kaur A, Mahajan M, Khichy S. Biomarkers of carcinoma breast in females. International Journal of Recent Scientific Research. 2015;2:2625-9.
- Belle L P, Bitencourt P E, Abdalla F H, Bona K S, Peres A, Maders L D, et al. Aqueous seed extract of Syzygium cumini inhibits the dipeptidyl peptidase IV and adenosine deaminase activities, but it does not change the CD26 expression in lymphocytes in vitro. J Physiol Biochem. 2013;69:119-24.
- Durak I, Biri H, Devrim E, Sozen S, Avci A. Aqueous extract of Urtica dioica makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer. Cancer Biol Ther. 2004;3:855-7.
- Durak Z E, Cubukcu H C, Buber S, Kocaoglu H, Durak I. Aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean exert different effects on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues. Journal of Health Research and Reviews. 2016;3:24.
- Ohta A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol. 2016;7:109.
- Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2017;36:293-303.
- Eisenstein A, Patterson S, Ravid K. The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases. J Cell Physiol. 2015;230:2891-7.
- Fishman P, Bar-Yehuda S, Synowitz M, Powell J D, Klotz K N, Gessi S, et al. Adenosine receptors and cancer. Handb Exp Pharmacol. 2009:399-441.
- Panjehpour M, Castro M, Klotz K N. Human breast cancer cell line MDA-MB-231 expresses endogenous A2B adenosine receptors mediating a Ca2+ signal. Br J Pharmacol. 2005;145:211-8.
- Meloche S, Pouyssegur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. 2007;26:3227-39.
- Katz M, Amit I, Yarden Y. Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta. 2007;1773:1161-76.
- Kahana C. Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor. Essays Biochem. 2009;46:47-61.
- Seiler N, Raul F. Polyamines and apoptosis. J Cell Mol Med. 2005;9:623-42.
- Tian H, Huang Q, Li L, Liu X X, Zhang Y. Gene expression of ornithine decarboxylase in lung cancers and its clinical significance. Acta Biochim Biophys Sin (Shanghai). 2006;38:639-45.
- Neto C C. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr. 2007;137:186S-93S.
- Sharma S K, Hazeldine S, Crowley M L, Hanson A, Beattie R, Varghese S, et al. Polyamine-based small molecule epigenetic modulators. Medchemcomm. 2012;3:14-21.
- Wei G, Hobbs C A, Defeo K, Hayes C S, Gilmour S K. Polyamine-mediated regulation of protein acetylation in murine skin and tumors. Mol Carcinog. 2007;46:611-7.
- Jalili C, Salahshoor M, Yousefi D, Khazaei M, Shabanizadeh Darehdori A, Mokhtari T. Morphometric and Hormonal Study of the Effect of Utrica diocia Extract on Mammary Glands in Rats. Int j morphol. 2015;33:983-7.
- Obiorah I E, Fan P, Jordan V C. Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state. Cancer Prev Res (Phila). 2014;7:939-49.
- Neve R M, Chin K, Fridlyand J, Yeh J, Baehner F L, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515-27.
- Yip K W, Reed J C. Bcl-2 family proteins and cancer. Oncogene. 2008;27:6398-406.
- Tor Y S, Yazan L S, Foo J B, Wibowo A, Ismail N, Cheah Y K, et al. Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile. PLoS One. 2015;10:e0127441.
References
Brown W, Ahnen D. The international health care burden of cancers of the gastrointestinal tract and liver. Cancer Res Front. 2014;1:1-9.
Amini Navaie B, Kavoosian S, Fattahi S, Hajian-Tilaki K, Asouri M, Bishekolaie R, et al. Antioxidant and Cytotoxic Effect of Aqueous and Hydroalcoholic Extracts of the Achillea Millefolium L. on MCF-7 Breast Cancer Cell Line. International Biological and Biomedical Journal. 2015;1:119-25.
Sharma G N, Dave R, Sanadya J, Sharma P, Sharma K K. Various types and management of breast cancer: an overview. J Adv Pharm Technol Res. 2010;1:109-26.
Coates A S, Winer E P, Goldhirsch A, Gelber R D, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26:1533-46.
Liao G S, Apaya M K, Shyur L F. Herbal medicine and acupuncture for breast cancer palliative care and adjuvant therapy. Evid Based Complement Alternat Med. 2013;2013:437948.
Ma H, Carpenter C L, Sullivan-Halley J, Bernstein L. The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors--results of a prospective study. BMC Cancer. 2011;11:222.
Fattahi S, Golpour M, Akhavan Niaki H. Urtica Dioica, An Emerauld in the Medical Kingdom. International Biological and Biomedical Journal. 2016;2:1-10.
Asgarpanah J, Mohajerani R. Phytochemistry and pharmacologic properties of Urtica dioica L. Journal of Medicinal Plants Research. 2012;6:5714-9.
Upton R. Stinging nettles leaf (Urtica dioica L.): Extraordinary vegetable medicine. Journal of Herbal Medicine. 2013;3:9-38.
Fattahi S, Ardekani A M, Zabihi E, Abedian Z, Mostafazadeh A, Pourbagher R, et al. Antioxidant and apoptotic effects of an aqueous extract of Urtica dioica on the MCF-7 human breast cancer cell line. Asian Pac J Cancer Prev. 2013;14:5317-23.
Tullo A, Mastropasqua G, Bourdon J C, Centonze P, Gostissa M, Costanzo A, et al. Adenosine deaminase, a key enzyme in DNA precursors control, is a new p73 target. Oncogene. 2003;22:8738-48.
Apasov S G, Blackburn M R, Kellems R E, Smith P T, Sitkovsky M V. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest. 2001;108:131-41.
Zhu Q, Jin L, Casero R A, Davidson N E, Huang Y. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells. Breast Cancer Res Treat. 2012;136:57-66.
Nowotarski S L, Woster P M, Casero R A, Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013;15:e3.
Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8-14.
Gerner E W, Meyskens F L, Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004;4:781-92.
Pandamooz S, Hadipour A, Akhavan-Niaki H, Pourghasem M, Abedian Z, Ardekani A M, et al. Short exposure to collagenase and coculture with mouse embryonic pancreas improve human dermal fibroblast culture. Biotechnol Appl Biochem. 2012;59:254-61.
Fattahi S, Amirbozorgi G, Lotfi M, Amini Navaei B, Kavoosian S, Asouri M, et al. Development of a Universal Taqman Probe for mRNA Gene Expression Analysis. Iranian Journal of Science and Technology, Transactions A: Science. [journal article]. 2017:1-8.
Fattahi S, Pilehchian Langroudi M, Samadani A A, Nikbakhsh N, Asouri M, Akhavan-Niaki H. Application of unique sequence index (USI) barcode to gene expression profiling in gastric adenocarcinoma. J Cell Commun Signal. 2017;11:97-104.
Shukla S, Mehta A. Anticancer potential of medicinal plants and their phytochemicals: a review. Brazilian Journal of Botany. [journal article]. 2015;38:199-210.
Keshavarz S, Ardekani M R S, Safavi M, Chahardouli B, Nadali F. In vitro cytotoxic effect of urtica dioica extracts on acute myelogenous leukemia cell line (kg-1). Archives of Medical Laboratory Sciences. 2016;2.
í‡agıl F Z, Akal Z U, Alpsoy L. Cytotoxic and Apoptotic Effects of Urticadioica Agglutinin on AGS Cells. . Med chem. 2015;5:124-9.
Ham J, Evans B A. An emerging role for adenosine and its receptors in bone homeostasis. Front Endocrinol (Lausanne). 2012;3:113.
Kaur A, Mahajan M, Khichy S. Biomarkers of carcinoma breast in females. International Journal of Recent Scientific Research. 2015;2:2625-9.
Belle L P, Bitencourt P E, Abdalla F H, Bona K S, Peres A, Maders L D, et al. Aqueous seed extract of Syzygium cumini inhibits the dipeptidyl peptidase IV and adenosine deaminase activities, but it does not change the CD26 expression in lymphocytes in vitro. J Physiol Biochem. 2013;69:119-24.
Durak I, Biri H, Devrim E, Sozen S, Avci A. Aqueous extract of Urtica dioica makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer. Cancer Biol Ther. 2004;3:855-7.
Durak Z E, Cubukcu H C, Buber S, Kocaoglu H, Durak I. Aqueous extracts of Rosmarinus officinalis, Urtica diocia, and soybean exert different effects on adenosine deaminase activity in cancerous and noncancerous human gastric and colon tissues. Journal of Health Research and Reviews. 2016;3:24.
Ohta A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol. 2016;7:109.
Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2017;36:293-303.
Eisenstein A, Patterson S, Ravid K. The Many Faces of the A2b Adenosine Receptor in Cardiovascular and Metabolic Diseases. J Cell Physiol. 2015;230:2891-7.
Fishman P, Bar-Yehuda S, Synowitz M, Powell J D, Klotz K N, Gessi S, et al. Adenosine receptors and cancer. Handb Exp Pharmacol. 2009:399-441.
Panjehpour M, Castro M, Klotz K N. Human breast cancer cell line MDA-MB-231 expresses endogenous A2B adenosine receptors mediating a Ca2+ signal. Br J Pharmacol. 2005;145:211-8.
Meloche S, Pouyssegur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. 2007;26:3227-39.
Katz M, Amit I, Yarden Y. Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta. 2007;1773:1161-76.
Kahana C. Regulation of cellular polyamine levels and cellular proliferation by antizyme and antizyme inhibitor. Essays Biochem. 2009;46:47-61.
Seiler N, Raul F. Polyamines and apoptosis. J Cell Mol Med. 2005;9:623-42.
Tian H, Huang Q, Li L, Liu X X, Zhang Y. Gene expression of ornithine decarboxylase in lung cancers and its clinical significance. Acta Biochim Biophys Sin (Shanghai). 2006;38:639-45.
Neto C C. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr. 2007;137:186S-93S.
Sharma S K, Hazeldine S, Crowley M L, Hanson A, Beattie R, Varghese S, et al. Polyamine-based small molecule epigenetic modulators. Medchemcomm. 2012;3:14-21.
Wei G, Hobbs C A, Defeo K, Hayes C S, Gilmour S K. Polyamine-mediated regulation of protein acetylation in murine skin and tumors. Mol Carcinog. 2007;46:611-7.
Jalili C, Salahshoor M, Yousefi D, Khazaei M, Shabanizadeh Darehdori A, Mokhtari T. Morphometric and Hormonal Study of the Effect of Utrica diocia Extract on Mammary Glands in Rats. Int j morphol. 2015;33:983-7.
Obiorah I E, Fan P, Jordan V C. Breast cancer cell apoptosis with phytoestrogens is dependent on an estrogen-deprived state. Cancer Prev Res (Phila). 2014;7:939-49.
Neve R M, Chin K, Fridlyand J, Yeh J, Baehner F L, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515-27.
Yip K W, Reed J C. Bcl-2 family proteins and cancer. Oncogene. 2008;27:6398-406.
Tor Y S, Yazan L S, Foo J B, Wibowo A, Ismail N, Cheah Y K, et al. Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile. PLoS One. 2015;10:e0127441.