Crocins: The Active Constituents of Crocus Sativus L. Stigmas, Exert Significant Cytotoxicity on Tumor Cells In Vitro

Author(s): Kyriaki Hatziagapiou, Eleni Kakouri, George I. Lambrou, Eleni Koniari, Charalabos Kanakis, Olti A. Nikola, Margarita Theodorakidou, Konstantinos Bethanis, Petros A. Tarantilis*.

Journal Name: Current Cancer Therapy Reviews

Volume 15 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Tumors of the childhood are considered to be grave and devastating pathologies, with high mortality rates. Current therapeutic options like cytotoxic drugs and radiotherapy target both healthy and malignant cells, thus resulting in long-term neurological and intellectual sequelae and endocrinological disorders.

Objectives: In this study, we focused on the anticancer potency of crocins, the main constituents of Crocus sativus L, stigmas. Crocins were first extracted using organic solvents from the dried stigmas and then were identified using the HPLC analysis.

Materials and Methods: TE-671 cells were treated with the extract of crocins using a range of concentrations between 0.25-mg/ mL and 16 mg/mL. Viability of the cells was measured at 24h, 48h, 72h and 96h. In addition, we have examined the expression levels of the p53 gene using Real-Time Reverse Transcription PCR.

Results: Results showed that crocins exerted significant cytotoxic and anti-proliferative effects in a concentration and time - dependent-manner on TE-671 cells. Furthermore, p53 manifested similar expression pattern as the anti-proliferative effect of crocin.

Conclusion: Our data demonstrate that crocins could be a novel promising agent for the improvement of tumor treatment.

Keywords: Saffron, crocins, cytotoxicity, anti-proliferation, tumor, CNS tumors, TE671.

[1]
Christodoulou E, Kadoglou NP, Kostomitsopoulos N, et al. Saffron: A natural product with potential pharmaceutical applications. J Pharm Pharmacol 2015; 67(12): 1634-49.
[2]
Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: Pharmacology and clinical uses. Wien Med Wochenschr 2007; 157(13-14): 315-9.
[3]
Hosseinzadeh H. Saffron: A herbal medicine of third millennium. Jundishapur J Nat Pharm Prod 2014; 9(1): 1-2.
[4]
Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: A comprehensive review. Food Chem Toxicol 2014; 64: 65-80.
[5]
Liakopoulou-Kyriakides M, Kyriakidis DA. Croscus sativus-biological active constitutents. Stud Nat Prod Chem 2002; 26: 293-312.
[6]
Assimopoulou AN, Sinakos Z, Papageorgiou VP. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005; 19(11): 997-1000.
[7]
Tarantilis PA, Tsoupras G, Polissiou M. Determination of saffron (Crocus sativus L.) components in crude plant extract using high-performance liquid chromatography-UV-visible photodiode-array detection-mass spectrometry. J Chromatogr A 1995; 699(1-2): 107-18.
[8]
Caballero-Ortega H, Pereda-Miranda R, Abdullaev FI. HPLC quantification of major active components from 11 different saffron (Crocus sativus L.) sources. Food Chem 2007; 100(3): 1126-31.
[9]
Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta 2014; 1845(1): 20-30.
[10]
Winterhalter P, Straubinger M. Saffron-renewed interest in an ancient spice. Food Rev Int 2000; 16(1): 39-59.
[11]
Abdullaev FI, Frenkel GD. The effect of saffron on intracellular DNA, RNA and protein synthesis in malignant and non-malignant human cells. Biofactors 1992; 4(1): 43-5.
[12]
Chryssanthi DG, Dedes PG, Karamanos NK, et al. Crocetin inhibits invasiveness of MDA-MB-231 breast cancer cells via downregulation of matrix metalloproteinases. Planta Med 2011; 77(2): 146-51.
[13]
Chryssanthi DG, Lamari FN, Iatrou G, et al. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer Res 2007; 27(1A): 357-62.
[14]
Lu P, Lin H, Gu Y, et al. Antitumor effects of crocin on human breast cancer cells. Int J Clin Exp Med 2015; 8(11): 20316-22.
[15]
Xia D. Ovarian cancer HO-8910 cell apoptosis induced by crocin in vitro. Nat Prod Commun 2015; 10(2): 249-52.
[16]
Chen S, Zhao S, Wang X, et al. Crocin inhibits cell proliferation and enhances cisplatin and pemetrexed chemosensitivity in lung cancer cells. Transl Lung Cancer Res 2015; 4(6): 775-83.
[17]
D’Alessandro AM, Mancini A, Lizzi AR, et al. Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr Cancer 2013; 65(6): 930-42.
[18]
Tavakkol-Afshari J, Brook A, and Mousavi SH. Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem Toxicol 2008; 46(11): 3443-7.
[19]
Abdullaev FI, Riveron-Negrete L, Caballero-Ortega H, et al. Use of in vitro assays to assess the potential antigenotoxic and cytotoxic effects of saffron (Crocus sativus L.). Toxicol In Vitro 2003; 17(5-6): 731-6.
[20]
Feizzadeh B, Afshari JT, Rakhshandeh H, et al. Cytotoxic effect of saffron stigma aqueous extract on human transitional cell carcinoma and mouse fibroblast. Urol J 2008; 5(3): 161-7.
[21]
Babaei A, Arshami J, Haghparast A, et al. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna J Phytomed 2014; 4(2): 103-9.
[22]
Bostan HB, Mehri S, Hosseinzadeh H. Toxicology effects of saffron and its constituents: A review. Iran J Basic Med Sci 2017; 20(2): 110-21.
[23]
Modaghegh MH, Shahabian M, Esmaeili HA, et al. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008; 15(12): 1032-7.
[24]
Mohamadpour AH, Ayati Z, Parizadeh MR, et al. Safety evaluation of Crocin (a constituent of saffron) tablets in healthy volunteers. Iran J Basic Med Sci 2013; 16(1): 39-46.
[25]
Ayatollahi H, Javan AO, Khajedaluee M, et al. Effect of Crocus sativus L. (saffron) on coagulation and anticoagulation systems in healthy volunteers. Phytother Res 2014; 28(4): 539-43.
[26]
Mousavi B, Bathaie SZ, Fadai F, et al. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed 2015; 5(5): 413-9.
[27]
Rahaiee S, Moini S, Hashemi M, et al. Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): A review. J Food Sci Technol 2015; 52(4): 1881-8.
[28]
Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005; 4(3): 206-20.
[29]
McAllister RM, Isaacs H, Rongey R, et al. Establishment of a human medulloblastoma cell line. Int J Cancer 1977; 20(2): 206-12.
[30]
Ivanov DP, Coyle B, Walker DA, et al. In vitro models of medulloblastoma: Choosing the right tool for the job. J Biotechnol 2016; 236: 10-25.
[31]
McAllister RM, Melnyk J, Finkelstein JZ, et al. Cultivation in vitro of cells derived from a human rhabdomyosarcoma. Cancer 1969; 24(3): 520-6.
[32]
Yeung CM, An BS, Cheng CK, et al. Expression and transcriptional regulation of the GnRH receptor gene in human neuronal cells. Mol Hum Reprod 2005; 11(11): 837-42.
[33]
Chu ES, Wong TK, Yow CM. Photodynamic effect in medulloblastoma: Downregulation of matrix metalloproteinases and human telomerase reverse transcriptase expressions. Photochem Photobiol Sci 2008; 7(1): 76-83.
[34]
Ramp U, Gerharz CD, Engers R, et al. Differentiation induction in the human rhabdomyosarcoma cell line TE-671. A morphological, biochemical and molecular analysis. Anticancer Res 1995; 15(1): 181-8.
[35]
Hoo RL, Chan KY, Leung FK, et al. Involvement of NF-kappaB subunit p65 and retinoic acid receptors, RARalpha and RXRalpha, in transcriptional regulation of the human GnRH II gene. FEBS J 2007; 274(11): 2695-706.
[36]
Mork SJ, May EE, Papasozomenos SC, et al. Characteristics of human medulloblastoma cell line TE-671 under different growth conditions in vitro: A morphological and immunohistochemical study. Neuropathol Appl Neurobiol 1986; 12(3): 277-89.
[37]
Petrenko YA, Gorokhova NA, Tkachova EN, et al. The reduction of Alamar Blue by peripheral blood lymphocytes and isolated mitochondria. Ukr Biokhim Zh (1999) 2005; 77(5): 100-5.
[38]
Adamaki M, Lambrou GI, Athanasiadou A, et al. Implication of IRF4 aberrant gene expression in the acute leukemias of childhood. PLoS One 2013; 8(8)e72326
[39]
Carmona M, Zalacain A, Sanchez AM, et al. Crocetin esters, picrocrocin and its related compounds present in Crocus sativus stigmas and Gardenia jasminoides fruits. Tentative identification of seven new compounds by LC-ESI-MS. J Agric Food Chem 2006; 54(3): 973-9.
[40]
Tarantilis PA, Polissiou M, Manfait M. Separation of picrocrocin, cis-trans-crocins and safranal of saffron using high-performance liquid chromatography with photodiode-array detection. J Chromatogr A 1994; 664(1): 55-61.
[41]
Osswald WF, Schutz W, and Elstner EF. Indole-3-acetic acid oxidation and crocin bleaching by horseradish peroxidase. Plant Physiol 1988; 86(4): 1310-4.
[42]
Speranza G, Dada G, Manitto P, et al. 13-Cis-Crocin-A new crocinoid of saffron. Gazz Chim Ital 1984; 114(3-4): 189-92.
[43]
Gumireddy K, Sutton LN, Phillips PC, et al. All-trans-retinoic acid-induced apoptosis in human medulloblastoma: Activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. Clin Cancer Res 2003; 9(11): 4052-9.
[44]
Hallahan AR, Pritchard JI, Chandraratna RA, et al. BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 2003; 9(8): 1033-8.
[45]
Spiller SE, Ditzler SH, Pullar BJ, et al. Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol 2008; 87(2): 133-41.
[46]
Bassani B, Bartolini D, Pagani A, et al. Fenretinide (4-HPR) Targets Caspase-9, ERK 1/2 and the Wnt3a/beta-Catenin Pathway in Medulloblastoma Cells and Medulloblastoma Cell Spheroids. PLoS One 2016; 11(7)e0154111
[47]
Bai R, Siu IM, Tyler BM, et al. Evaluation of retinoic acid therapy for OTX2-positive medulloblastomas. Neuro-oncol 2010; 12(7): 655-63.
[48]
Di C, Liao S, Adamson DC, et al. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res 2005; 65(3): 919-24.
[49]
Wortham M, Guo C, Zhang M, et al. Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma. PLoS One 2014; 9(9)e107156
[50]
Masetti R, Biagi C, Zama D, et al. Retinoids in pediatric onco-hematology: The model of acute promyelocytic leukemia and neuroblastoma. Adv Ther 2012; 29(9): 747-62.
[51]
Mawson AR. Retinoids in the treatment of glioma: A new perspective. Cancer Manag Res 2012; 4: 233-41.
[52]
Reynolds CP. Differentiating agents in pediatric malignancies: retinoids in neuroblastoma. Curr Oncol Rep 2000; 2(6): 511-8.
[53]
Reynolds CP, and Lemons RS. Retinoid therapy of childhood cancer. Hematol Oncol Clin North Am 2001; 15(5): 867-910.
[54]
Gundimeda U, Hara SK, Anderson WB, Gopalakrishna R. Retinoids inhibit the oxidative modification of protein kinase C induced by oxidant tumor promoters. Arch Biochem Biophys 1993; 300(1): 526-30.
[55]
Reynolds CP, Matthay KK, Villablanca JG, et al. Retinoid therapy of high-risk neuroblastoma. Cancer Lett 2003; 197(1-2): 185-92.
[56]
Siddikuzzaman, Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol 2011; 33(2): 241-9.
[57]
Luo Y, Cui S, Tang F, et al. The combination of crocin with cisplatin suppresses growth of gastric carcinoma cell line BGC-823 and promotes cell apoptosis. Pak J Pharm Sci 2017; 30(5): 1629-34.
[58]
Mollaei H, Safaralizadeh R, Babaei E, et al. The anti-proliferative and apoptotic effects of crocin on chemosensitive and chemoresistant cervical cancer cells. Biomed Pharmacother 2017; 94: 307-16.
[59]
Ashrafi M, Bathaie SZ, Abroun S, et al. Effect of crocin on cell cycle regulators in N-nitroso-N-methylurea-induced breast cancer in rats. DNA Cell Biol 2015; 34(11): 684-91.
[60]
Vali F, Changizi V, and Safa M. Synergistic apoptotic effect of crocin and paclitaxel or crocin and radiation on MCF-7 cells, a type of breast cancer cell line. Int J Breast Cancer 2015; 2015139349
[61]
Patel S, Sarwat M, Khan TH. Mechanism behind the anti-tumour potential of saffron (Crocus sativus L.): The molecular perspective. Crit Rev Oncol Hematol 2017; 115: 27-35.
[62]
Bukhari SI, Manzoor M, Dhar MK. A comprehensive review of the pharmacological potential of Crocus sativus and its bioactive apocarotenoids. Biomed Pharmacother 2018; 98: 733-45.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [225 - 234]
Pages: 10
DOI: 10.2174/1573394714666181029120446
Price: $65

Article Metrics

PDF: 22
HTML: 4
EPUB: 1
PRC: 1