Crocetin as an Active Secondary Metabolite of Saffron Stigma and Anticancer Effects

Author(s): Ali Farahi, Homa Mollaei*, Reyhane Hoshyar*.

Journal Name: Current Cancer Therapy Reviews

Volume 15 , Issue 3 , 2019

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Graphical Abstract:


In order to try to increase the effectiveness of cancer therapeutic procedures, natural carotenoids attract lots of attention. Crocetin is one of the main carotenoids of saffron whose anticancer properties have been shown in recent decades. This study aimed to review previous in vitro and in vivo investigations on anticancer effects of this carotenoid and also proposed molecular mechanisms of its action. Literature reviewing between 1990 and 2017 was performed using pubmed and scopus databases. Anti-proliferative and pro-apoptotic effects of crocetin have been observed in several cancers cell lines and also model organisms that might be due to the alternation in the expression of cancer-related genes and epigenetic changes. Moreover, several studies indicated synergistic effects of crocetin with common chemotherapy agents and mentioned it as a potential novel adjuvant therapy.

Keywords: Crocetin, anticancer, chemotherapy, pro-apoptotic, metabolite, carotenoids.

Hoshyar R, Mollaei H. A comprehensive review on anticancer mechanisms of the main carotenoid of saffron, crocin. J Pharm Pharmacol 2017; 69(11): 1419-27.
Mollaei H, Babaei E. Therapeutic potential of novel nano-based curcumin compounds in vitro and in vivo. APJCP 2017; 18(4): 885.
Ebrahimi S, Mollaei H, Hoshyar R. Ziziphus Jujube: A review study of its anticancer effects in various tumor models in vitro and in vivo. Cell Mol Biol 2017; 63(10): 122-7.
Hoshyar R, Jamali S, Fereidouni M, Abedini MR. The cytotoxic activity of Ziziphus Jujube on cervical cancer cells: In vitro study. Cell Mol Biol 2015; 61(8): 128-30.
Chabner BA, Roberts Jr TG. Chemotherapy and the war on cancer. Nat Rev Cancer 2005; 5(1): 65.
Hung KF, Hsu CP, Chiang JH, et al. Complementary Chinese herbal medicine therapy improves survival of patients with gastric cancer in Taiwan: A nationwide retrospective matched-cohort study. J Ethnopharmacol 2017; 199: 168-74.
Mollaei H, Safaralizadeh R, Babaei E, Abedini MR, Hoshyar R. The anti-proliferative and apoptotic effects of crocin on chemosensitive and chemoresistant cervical cancer cells. Biomed Pharmacother 2017; 94: 307-16.
Keerthy JN, Anbu N, Moses SI. A review on selective herbs for the management of pancreatic cancer. Imperial J Interdisciplin Res 2017; 3: 8.
Haghi A, Azimi H, Rahimi R. A comprehensive review on pharmacotherapeutics of three phytochemicals, curcumin, quercetin, and allicin, in the treatment of gastric cancer. J Gastrointest Cancer 2017; 48(4): 314-20.
Mostafavinia SE, Khorashadizadeh M, Hoshyar R. Antiproliferative and proapoptotic effects of crocin combined with hyperthermia on human breast cancer cells. DNA Cell Biol 2016; 35(7): 340-7.
Hoshyar R, Mahboob Z, Zarban A. The antioxidant and chemical properties of Berberis vulgaris and its cytotoxic effect on human breast carcinoma cells. Cytotechnology 2016; 68(4): 1207-13.
Bathaie SZ, Farajzade A, Hoshyar R. A review of the chemistry and uses of crocins and crocetin, the carotenoid natural dyes in saffron, with particular emphasis on applications as colorants including their use as biological stains. Biotech Histochem 2014; 89(6): 401-11.
Giuliano G. Plant carotenoids: Genomics meets multi-gene engineering. Curr Opin Plant Biol 2014; 19: 111-7.
Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta 2014; 1845(1): 20-30.
Hoshyar R, Khayati GR, Poorgholami M, Kaykhaii M. A novel green one-step synthesis of gold nanoparticles using crocin and their anti-cancer activities. J Photochem Photobiol B Biol 2016; 159: 237-42.
Bathaie SZ, Hoshyar R, Miri H, Sadeghizadeh M. Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer. Biochem Cell Biol 2013; 91(6): 397-403.
Rahaiee S, Moini S, Hashemi M, Shojaosadati SA. 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.
Poma A, Fontecchio G, Carlucci G, Chichiricco G. Anti-inflammatory properties of drugs from saffron crocus. Antiinflamm Antiallergy Agents Med Chem 2012; 11(1): 37-51.
Mancini A, Serrano-Díaz J, Nava E, et al. Crocetin, a carotenoid derived from saffron (Crocus sativus L.), improves acetylcholine-induced vascular relaxation in hypertension. J Vasc Res 2014; 51(5): 393-404.
Xu Ql, Qian Zy. Experimental study on anticoagulability and antithrombotic activity of crocetin. Chinese Tradition Herb Drugs 2007; 1031
Yan J, Qian Z, Sheng L, et al. Effect of crocetin on blood pressure restoration and synthesis of inflammatory mediators in heart after hemorrhagic shock in anesthetized rats. Shock 2010; 33(1): 83-7.
Chen P, Chen Y, Wang Y, et al. Comparative evaluation of hepatoprotective activities of geniposide, crocins and crocetin by CCl4-induced liver injury in mice. Biomol Therapeut 2016; 24(2): 156.
Samini F, Samarghandian S. Neuroprotective effects of Crocus Sativus L. and its main constituents. Der Pharma Lett 2016; 8(13): 25-9.
Moradzadeh M, Sadeghnia HR, Tabarraei A, Sahebkar A. Anti‐tumor effects of crocetin and related molecular targets. J Cell Physiol 2017; 233(3): 2170-82.
Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA 2017; 67(3): 177-93.
Kaur R, Kapoor K, Kaur H. Plants as a source of anticancer agents. J Nat Prod Plant Resour 2011; 1(1): 119-24.
Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol 2012; 30(7): 679.
Behdani MA, Hoshyar R. Phytochemical properties of Iranian organic saffron stigma: Antioxidant, anticancer and apoptotic approaches. Cell Mol Biol 2016; 62: 14.
Magesh V, Singh JP, Selvendiran K, Ekambaram G, Sakthisekaran D. Antitumour activity of crocetin in accordance to tumor incidence, antioxidant status, drug metabolizing enzymes and histopathological studies. Mol Cell Biochem 2006; 287(1-2): 127-35.
Dhar A, Mehta S, Dhar G, et al. Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Mol Cancer Ther 2009; 8(2): 315-23.
Li S, Shen XY, Ouyang T, Qu Y, Luo T, Wang HQ. Synergistic anticancer effect of combined crocetin and cisplatin on KYSE-150 cells via p53/p21 pathway. Cancer Cell Int 2017; 17(1): 98.
Ashrafi M, Bathaie SZ, Taghikhani M, Moosavi-Movahedi AA. The effect of carotenoids obtained from saffron on histone H1 structure and H1–DNA interaction. Int J Biol Macromol 2005; 36(4): 246-52.
Wang H-F, Ma J-X, Shang Q-L, An J-B, Chen H-T. crocetin inhibits the proliferation, migration and Tgf-β2-induced epithelial-mesenchymal transition of retinal pigment epithelial cells. Eur J Pharmacol 2017; 815: 391-8.
Li S, Jiang S, Jiang W, et al. Anticancer effects ofcrocetin in human esophageal squamous cell carcinoma KYSE-150 cells. Oncol Lett 2015; 9(3): 1254-60.
Kim SH, Lee JM, Kim SC, Park CB, Lee PC. Proposed cytotoxic mechanisms of the saffron carotenoids crocin and crocetin on cancer cell lines. Biochem Cell Biol 2014; 92(2): 105-11.
Jagadeeswaran R, Thirunavukkarasu C, Gunasekaran P, Ramamurty N, Sakthisekaran D. In vitro studies on the selective cytotoxic effect of crocetin and quercetin. Fitoterapia 2000; 71(4): 395-9.
Morjani H, Tarantilis P, Polissiou M, Manfait M. Growth inhibition and induction of crythroid differentiation activity by crocin, dimethylcrocetine and b-carotene on K562 tumor cells. Anticancer Res 1990; 10: 1398-406.
Umigai N, Tanaka J, Tsuruma K, Shimazawa M, Hara H. Crocetin, a carotenoid derivative, inhibits VEGF-induced angiogenesis via suppression of p38 phosphorylation. Curr Neurovasc Res 2012; 9(2): 102-9.
Zhang A, Li J. Crocetin shifts autophagic cell survival to death of breast cancer cells in chemotherapy. Tumor Biol 2017; 39(3)1010428317694536
Abdullaev FI. Inhibitory effect of crocetinon intracellular nucleic acid and protein synthesis in malignant cells. Toxicol Lett 1994; 70(2): 243-51.
Hoshyar R, Bathaie SZ, Kyani A, Mousavi MF. Is there any interaction between telomeric DNA structures, G-quadruplex and I-motif, with saffron active metabolites? Nucleosides Nucleotides Nucleic Acids 2012; 31(11): 801-12.
Tseng T-H, Chu C-Y, Huang J-M, Shiow S-J, Wang C-J. Crocetin protects against oxidative damage in rat primary hepatocytes. Cancer Lett 1997; 1: 61-7.
Langroodi F, Hafezi Ghahestani Z, Alibolandi M, Ebrahimian M, Hashemi M. Evaluation of the effect of crocetin on antitumor activity of doxorubicin encapsulated in PLGA nanoparticles. Nanomed J 2016; 3(1): 23-34.
Magesh V. DurgaBhavani K, Senthilnathan P, Rajendran P, Sakthisekaran D. In vivo protective effect of crocetin on benzo (a) pyrene‐induced lung cancer in Swiss albino mice. Phytother Res 2009; 23(4): 533-9.
Wang CJ, Cheng TC, Liu JY, Chou FP, Kuo ML, Lin JK. Inhibition of protein kinase C and proto‐oncogene expression by crocetin in NIH/3T3 cells. Mol Carcinog 1996; 17(4): 235-40.
Gainer J, Wallis D, Jones J. The effect of crocetin on skin papillomas and Rous sarcoma. Oncology 1976; 6(5): 222-4.
Sajjadi M, Bathaie Z. Comparative study on the preventive effect of saffron carotenoids, crocin and crocetin, in NMU-induced breast cancer in rats. Cell J 2017; 19(1): 94.
Martin G, Goh E, Neff A. Evaluation of the developmental toxicity of crocetin on Xenopus. Food Chem Toxicol 2002; 40(7): 959-64.
Wang C-J, Shiow S-J, Lin J-K. Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. Carcinogenesis 1991; 12(3): 459-62.
Wang C-J, Hsu J-D, Lin J-K. Suppression of aflatoxin B1-induced hepatotoxic lesions by crocetin (a natural carotenoid). Carcinogenesis 1991; 12(10): 1807-10.
Nair S, Panikkar K, Parthod R. Protective effects of crocetin on the bladder toxicity induced by cyclophosphamide. Cancer Biother Radiopharm 1993; 8(4): 339-43.
Nair SC, Panikkar KR, Parthod RK. Protective effects of crocetin on the bladder toxicity induced by cyclophosphamide. Cancer Biother 1993; 8(4): 339-43.
Zhuang X, Dong A, Wang R, Shi A. Crocetin treatment inhibits proliferation of colon cancer cells through down-regulation of genes involved in the inflammation. Saudi J Biol Sci 2018; 25(8): 1767-71.
Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK, Cordopatis P. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer Res 2007; 27: 357-62.

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Year: 2019
Page: [192 - 196]
Pages: 5
DOI: 10.2174/1573394714666180626154833
Price: $65

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