Role of crocin in several cancer cell lines: An updated review

Document Type: Review Article

Authors

1 Behbahan Faculty of Medical Sciences, Behbahan, Iran

2 Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

3 Research Center for Infectious Diseases of Digestive System [Alimentary Tract Research Center], Physiology Research Center (PRC), Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of pediatrics, Behbahan Faculty of Medical Sciences, Behbahan, Iran

5 Department of Physiology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

Abstract

Cancer is a major public health problem worldwide. The most important considerable features of cancer cells are uncontrolled proliferation, up-regulated differentiation, and immortality. Crocin, as a bioactive compound of saffron and as a water-soluble carotenoid has radical scavenging, anti-hyperlipidemia, memory improving, and inhibition of tumor growth effects. The present review was designed to evaluate molecular mechanisms underlying crocin effects against cancer cell lines. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, and Scientific Information Database from 1982 to 2019. According to various literature, crocin inhibits tumor growth, and its spread in several types of cancer including colorectal, pancreatic, breast, and prostate, as well as chronic myelogenous and leukemia. It inhibits telomerase activity, microtubule polymerization, cyclin D1, nuclear factor kappa B (NF-kB), multidrug resistance-associated protein (MRP1), and MRP2 overexpression. Crocin can induce apoptosis through activation of caspase 8, up-regulation of p53 expression, Bax/Bcl-2 ratio, and down-regulation expression of Bcl-2, survivin, and cyclin D1. It also down-regulates matrix metalloproteinase 2 and 9 (MMP2 and MMP9), N-cadherin, and beta-catenin expression, which are involved in tumor invasion and metastasis. Tumor invasion was also inhibited by crocin through increasing E-cadherin expression, cell cycle suppression at G1, G0/G1, S, and G2/M phases. Crocin has therapeutic and preventive effects on cancer cells line. Therefore, it has been suggested that this agent can be administered in patients that suffer from this problem.

Keywords


1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2015;65:5-29.
2. Johnson IT. Phytochemicals and cancer. Proc Nutr Soc 2007;66:207-215.
3. Bostan HB, Mehri S, Hosseinzadeh H. Toxicology effects of saffron and its constituents: a review. Iran J Basic Med Sci 2017;20:110-121
4. 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;89:401-411.
5. Mard SA, Akbari G, Dianat M, Mansouri E. Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study. Biomed Pharmacother 2017;96:48-55.
6. Hosseini A, Razavi BM, Hosseinzadeh H. Saffron (Crocus sativus) petal as a new pharmacological target: a review. Iran J Basic Med Sci 2018;21:1091-1099.
7. Iborra J, Castellar MR, Cánovas MA, Manjón AR. TLC preparative purification of picrocrocin, HTCC and crocin from saffron. J Food Sci 1992;57:714-716.
8. Mard SA, Akbari G, Mansouri E, Parsanahad M. Renoprotective effect of crocin following liver ischemia/reperfusion injury in Wistar rats. Iran J Basic Med Sci 2017;20:1172-1177.
9. Xi L, Qian Z, Du P, Fu J. Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine 2007;14:633-636.
10. Asai A, Nakano T, Takahashi M, Nagao A. Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. J Agric Food Chem 2005;53:7302-7306.
11. Hosseinzadeh H, Mehri S, Heshmati A, Ramezani M, Sahebkar A, Abnous K. Proteomic screening of molecular targets of crocin. Daru 2014;22:5-14.
12. Ochiai T, Soeda S, Ohno S, Tanaka H, Shoyama Y, Shimeno H. Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis. Neurochem Int 2004;4:321-330.
13. Chen Y, Yang T, Huang J, Tian X, Zhao C, Cai L, et al. Comparative evaluation of the anti-oxidant capacity of crocetin and crocin in vivo. Chin Pharm Bull 2010; 26:248-251.
14. Hosseinzadeh H, Shamsaie F, Mehri S. Anti-oxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Pharmacogn Mag 2009;5:419-424.
15. Dar RA, Brahman PK, Khurana N, Wagay JA, Lone ZA, Ganaie MA, et al. Evaluation of anti-oxidant activity of crocin, podophyllotoxin and kaempferol by chemical, biochemical and electrochemical assays. Arab J Chem 2017;10 :S1119–S1128.
16. Akbari G, Mard SA, Dianat M. Effect of crocin on cardiac anti-oxidants, and hemodynamic parameters after injuries induced by hepatic ischemia-reperfusion in rats. Iran J Basic Med Sci 2019;22:277-281.
17. Yarijani ZM, Najafi H, Madani SH. Protective effect of crocin on gentamicin-induced nephrotoxicity in rats. Iran J Basic Med Sci 2016;19:337–343.
18. Akbari G, Mard SA, Veisi A. A comprehensive review on regulatory effects of crocin on ischemia/reperfusion injury in multiple organs. Biomed Pharmacother 2018;99:664-670.
19. Nam KN, Park Y-M, Jung H-J, Lee JY, Min BD, Park S-U, et al. Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 2010;648:110-116.
20. Xu G-L, Li G, Ma H-P, Zhong H, Liu F, Ao G-Z. Preventive effect of crocin in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem 2009;57:8325-8330.
21. Yarijani ZM, Pourmotabbed A, Pourmotabbed T, Najafi H. Crocin has anti-inflammatory and protective effects in ischemia-reperfusion induced renal injuries. Iran J Basic Med Sci 2017;20:753–759.
22. Kim JH, Park GY, Bang SY, Park SY, Bae SK, Kim Y. Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4. Mediators Inflamm 2014;2014:728709.
23. Sebastin Santhosh M, Hemshekhar M, Thushara RM, Devaraja S, Kemparaju K, Girish KS. Vipera russelli venom-induced oxidative stress and hematological alterations: Amelioration by crocin a dietary colorant. Cell Biochem Funct 2013;31:41-50.
24. Park JH, Lee KY, Park B, Yoon J. Suppression of Th2 chemokines by crocin via blocking of ERK-MAPK/NF-κB/STAT1 signalling pathways in TNF-α/IFN-γ-stimulated human epidermal keratinocytes. Exp Dermatol 2015;24:634-636.
25. Kim B, Lee KY, Park B. Crocin suppresses constitutively active STAT3 through induction of protein tyrosine phosphatase SHP‐1. J Cell Biochem 2017;118:3290-3298.
26. Vahdati Hassani F, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. Daru 2014;22:16-24.
27. Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, et al. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 2011;667:222-229.
28. Heidari S, Mehri S, Hosseinzadeh H. Memory enhancement and protective effects of crocin against D-galactose aging model in the hippocampus of Wistar rats. Iran J Basic Med Sci 2017;20:1250-1259.
29. Kamyar M, Razavi BM, Hasani FV, Mehri S, Foroutanfar A, Hosseinzadeh H. Crocin prevents haloperidol-induced orofacial dyskinesia: possible an anti-oxidant mechanism. Iran J Basic Med Sci 2016;19:1070-1079.
30. Cao PC, Xiao WX, Yan YB, Zhao X, Liu S, Feng J, et al. Preventive effect of crocin on osteoporosis in an ovariectomized rat model. Evid Based Complement Alternat Med 2014;2014:825181.
31. Thomas H. Colorectal cancer: Calcineurin drives CRC tumorigenesis. Nat Rev Gastroenterol Hepatol 2016;13:249.
32. haram JF, Zhang F, Landon BE, LeCates R, Soumerai S, Ross-Degnan D. Colorectal cancer screening in a nationwide high-deductible health plan before and after the Affordable Care Act. Med Care 2016;54:466-473.
33. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, et al. Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp Oncol 2007;29:175-180.
34. Amin A, Bajbouj K, Koch A, Gandesiri M, Schneider-Stock R. Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis. Int J Mol Sci 2015;16:1544-1561.
35. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-344.
36. McConnell BB, Yang VW. The role of inflammation in the pathogenesis of colorectal cancer. Curr Colorectal Cancer Rep 2009;5:69-74.
37. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002;2:725-734.
38. Lin A, Karin M, editors. NF-kappaB in cancer: a marked target. Semin Cancer Biol 2003;13:107-114.
39. Olivier S, Robe P, Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol 2006;72:1054-1068.
40. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-1107.
41. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 2006;66:11580-11584.
42. Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, et al. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila) 2008;1:187-191.
43. Osburn WO, Karim B, Dolan PM, Liu G, Yamamoto M, Huso DL, et al. Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2‐deficient mice upon dextran sulfate treatment. Int J Cancer 2007;121:1883-1891.
44. Hu R, Saw CL, Yu R, Kong AN. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: anti-oxidant coupled with antiinflammatory. Antioxid Redox Signal 2010;13:1679-1698.
45. Hemshekhar M, Sebastin Santhosh M, Sunitha K, Thushara RM, Kemparaju K, Rangappa KS, et al. A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and anti-oxidant status. Biochimie 2012;94:2723-2733.
46. Amin A, Hamza AA, Daoud S, Khazanehdari K, Hrout AA, Baig B, et al. Saffron-based crocin prevents early lesions of liver cancer: In vivo, in vitro and network analyses. Recent Pat Anticancer Drug Discov 2016;11:121-133.
47. Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evid Based Complement Alternat Med 2012;2012:820415.
48. Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest 2008;118:2516-2525.
49. Bakshi HA, Hakkim FL, Sam S. Molecular mechanism of Crocin induced caspase mediated MCF-7 cell death: in vivo toxicity profiling and ex vivo macrophage activation. Asian Pac J Cancer Prev 2016;17:1499-506.
50. Mostafavinia SE, Khorashadizadeh M, Hoshyar R. Antiproliferative and proapoptotic effects of crocin combined with hyperthermia on human breast cancer cells. DNA Cell Biol 2016;35:340-347.
51. Vali F, Changizi V, 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;2015:139349.
52. Hoshyar R, Mollaei H. A comprehensive review on anticancer mechanisms of the main carotenoid of saffron, crocin. J Pharm Pharmacol 2017;69:1419-1427.
53. Festuccia C, Mancini A, Gravina GL, Scarsella L, Llorens S, Alonso GL, et al. Antitumor effects of saffron-derived carotenoids in prostate cancer cell models. Biomed Res Int 2014;2014:135048.4.
54. D’Alessandro AM, Mancini A, Lizzi AR, De Simone A, Marroccella CE, Gravina GL, et al. Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr Cancer 2013;65:930-942.
55. Noureini SK, Wink M. Antiproliferative effects of crocin in HepG2 cells by telomerase inhibition and hTERT down-regulation. Asian Pac J Cancer Prev 2012;13:2305-3509.
56. Escribano J, Alonso GL, Coca-Prados M, Fernández JA. Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett 1996;100:23-30.
57. Sun J, Xu XM, Ni CZ, Zhang H, Li XY, Zhang CL, et al. Crocin inhibits proliferation and nucleic acid synthesis and induces apoptosis in the human tongue squamous cell carcinoma cell line Tca8113. Asian Pac J Cancer Prev 2011;12:2679-2683.
58. Ghoussaini M, Pharoah PDP, Easton DF. Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning? Am J Pathol 2013;183:1038-1051.
59. Bakshi HA, Hakkim FL, Sam S. Molecular mechanism of crocin induced caspase mediated MCF-7 cell death: In vivo toxicity profiling and Ex vivo macrophage activation. Asian Pac J Cancer Prev 2016;17:1499-1506.
60. Lu P, Lin H, Gu Y, Li L, Guo H, Wang F, et al. Antitumor effects of crocin on human breast cancer cells. Int J Clin Exp Med 2015;8:20316-20322.
61. Green DR. Apoptotic pathways: paper wraps stone blunts scissors. Cell 2000;102:1-4.
62. Burz C, Berindan-Neagoe I, Balacescu O, Irimie A. Apoptosis in cancer: key molecular signaling pathways and therapy targets. Acta Oncol 2009;48:811-821.
63. Ivana Scovassi A, Diederich M. Modulation of poly(ADP-ribosylation) in apoptotic cells. Biochem Pharmacol 2004 ;68:1041-1047.
64. Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JP, Melendez-Zajgla J. Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res 2008;27:48.
65. Zhang MC, Liu HP, Demchik LL, Zhai YF, Yang DJ. LIGHT sensitizes IFN-gamma-mediated apoptosis of HT-29 human carcinoma cells through both death receptor and mitochondria pathways. Cell Res 2004;14:117-124.
66. Hsu H-F, Houng J-Y, Kuo C-F, Tsao N, Wu Y-C. Glossogin, a novel phenylpropanoid from Glossogyne tenuifolia, induced apoptosis in A549 lung cancer cells. Food Chem Toxicol 2008;46:3785-3791.
67. Tyagi AK, Agarwal C, Chan DC, Agarwal R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep 2004;11:493-499.
68. Tyagi AK, Singh RP, Agarwal C, Chan DC, Agarwal R. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin Cancer Res 2002;8:3512-3519
69. Velasco-Velázquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of cyclin D1 in breast cancer. Future Oncol 2011;7:753-765.
70. Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M. NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999;19:2690-2698.
71. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 1997;272:10882-10894.
72. Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994;369:669-671.
73. Umekita Y, Ohi Y, Sagara Y, Yoshida H. Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor-negative breast cancer patients. Int J Cancer 2002;98:415-418.
74. Ashrafi M1, Bathaie SZ, Abroun S, Azizian M. Effect of crocin on cell cycle regulators in N-nitroso-N-methylurea-induced breast cancer in rats. DNA Cell Biol 2015;34:684-691.
75. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817-825.
76. Dai M, Al-Odaini AA, Fils-Aimé N, Villatoro MA, Guo J, Arakelian A, et al. Cyclin D1 cooperates with p21 to regulate TGFβ-mediated breast cancer cell migration and tumor local invasion. Breast Cancer Res 2013;15:R49.
77. Zarei Jaliani H, Riazi GH, Ghaffari SM, Karima O, Rahmani A. The effect of the crocus sativus L. Carotenoid, crocin, on the polymerization of microtubules, in vitro. Iran J Basic Med Sci 2013;16:101-107.
78. Avila J. Microtubule functions. Life Sci 1992;50:327-334.
79. Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 2010;9:790-803.
80. Zhang D, Yang R, Wang S, Dong Z. Paclitaxel: new uses for an old drug. Drug Des Devel Ther 2014;8:279-284.
81. Hire RR, Srivastava S, Davis MB, Kumar Konreddy A, Panda D. Antiproliferative activity of crocin involves targeting of microtubules in breast cancer cells. Sci Rep 2017;7:44984.
82. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A cancer journal for clinicians. CA Cancer J Clin 2016 ;66:7-30.
83. Esposito L, Conti D, Ailavajhala R, Khalil N, Giordano A. Lung Cancer: Are we up to the challenge? Curr Genomics 2010;11:513-518.
84. Takiguchi Y, Sekine I, Iwasawa S, Kurimoto R, Tatsumi K. Chronic obstructive pulmonary disease as a risk factor for lung cancer. World J Clin Oncol 2014;5:660-666.
85. Sheen S, Lee KS, Chung WY, Nam S, Kang DR. An updated review of case–control studies of lung cancer and indoor radon-Is indoor radon the risk factor for lung cancer? Ann Occup Environ Med 2016;28:1-9.
86. Samarghandian S, Borji A, Farahmand SK, Afshari R, Davoodi S. Crocus sativus L.(saffron) stigma aqueous extract induces apoptosis in alveolar human lung cancer cells through caspase-dependent pathways activation. Biomed Res Int 2013;2013:417928.
87. Chen S, Zhao S, Wang X, Zhang L, Jiang E, Gu Y, et al. Crocin inhibits cell proliferation and enhances cisplatin and pemetrexed chemosensitivity in lung cancer cells. Transl Lung Cancer Res 2015;4:775-783.
88. Stein U, Schlag PM. Clinical, biological, and molecular aspects of metastasis in colorectal cancer.  Recent Results Cancer Res 2007;176:61-80.
89. D’Alessandro AM, Mancini A, Lizzi AR, De Simone A, Marroccella CE, Gravina GL, et al. Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr Cancer 2013;65:930-942.
90. Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci 2003;94:575-581.
91. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene 2005;24:7443-7454.
92. Kang Y, Massagué J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004 6;118:277-279.
93. Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006;66:8319-8326.
94. Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia 2010;15:201-212.
95. Chuang SC, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 2009;286:9-14.
96. Smith LL, Coller HA, Roberts JM. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol 2003;5:474-479.
97. Noureini SK, Wink M. Antiproliferative effects of crocin in HepG2 cells by telomerase inhibition and hTERT down-regulation. Asian Pac J Cancer Prev 2012;13:2305-2309.
98. Moreno-Acosta P, Gamboa O, Mayorga D, Romero A, Acosta J, Sanabria MC, et al. Prognostic biomarkers as molecular targets for individualized neoadjuvant treatment for cervical cancer. Eur J Cancer 2016;69:S40.
99. Inoue M, Ogawa H, Miyata M, Shiozaki H, Tanizawa O. Expression of E-cadherin in normal, benign, and malignant tissues of female genital organs. Am J Clin Pathol 1992;98:76-80.
100. Valavi M, Saedabad A, Hoshyar R, Mollaei H. Effects of combined crocin and epirubicin on apoptosis and cell cycle pathways in a human cervical cancer cell line. Int J Cancer Manag 2018;11:e82575.
101. Bridson RH, Santos RC, Al-Duri B, McAllister SM, Robertson J, Alpar HO. The preparation of liposomes using compressed carbon dioxide: strategies, important considerations and comparison with conventional techniques. J Pharm Pharmacol 2006;58:775-785.
102. Mousavi SH, Moallem SA, Mehri S, Shahsavand S, Nassirli H, Malaekeh-Nikouei B. Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form. Pharm Biol. 2011;49:1039-1045.
103. 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;92:105-111.
104. Akbari G, Mard SA, Dianat M, Mansouri E. The hepatoprotective and microRNAs downregulatory effects of crocin following hepatic ischemia-reperfusion injury in rats. Oxid Med Cell Longev 2017;2017:1702967.
105. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 2008;68:1303-1309.
106. Bayley JP, Devilee P. The Warburg effect in 2012. Curr Opin Oncol 2012;24:62-67.
107. Arseneault R, Chien A, Newington JT, Rappon T, Harris R, Cumming RC. Attenuation of LDHA expression in cancer cells leads to redox-dependent alterations in cytoskeletal structure and cell migration. Cancer Lett 2013;338:255-266.
108. Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006;9:425-4434.
109. Guo J, Cahill MR, McKenna SL, O’Driscoll CM. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia. Biotechnol Adv. 2014;32:1396-1409.
110. Ethier MC, Blanco E, Lehrnbecher T, Sung L. Lack of clarity in the definition of treatment-related mortality: pediatric acute leukemia and adult acute promyelocytic leukemia as examples. Blood 2011;118:5080-5083.
111. Sun Y, Xu HJ, Zhao YX, Wang LZ, Sun LR, Wang Z, et al. Crocin exhibits antitumor effects on human leukemia HL-60 cells in vitro and in vivo. Evid Based Complement Alternat Med 2013;2013:690164.
112. Sun Y, Wang Z, Wang L, Wang LZ, Zang C, Sun LR. The effect and mechanisms of proliferative inhibition of crocin on human leukaemia jurkat cells. West Indian Med J 2015;64:473-479.
113. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 201;364:1046-1060.
114. Rezaee R, Jamialahmadi K, Riahi Zanjani B, Mahmoudi M, Abnous K, Zamani Taghizadeh Rabe S, et al. Crocin effects on human myeloma cells regarding intracellular redox state, DNA fragmentation, and apoptosis or necrosis profile. Jundishapur J Nat Pharm Prod 2014;9:e20131.
115. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005;5:761-772.
116. Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci 2007;32:517-530.
117. Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 1998;12:3788-3796.
118. Ghayour-Mobarhan M, Saber H, Ferns GA. The potential role of heat shock protein 27 in cardiovascular disease. Clin Chim Acta 2012;413:15-24.
119. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-236.
120. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. European Journal of Pharmaceutical Sciences 2000;11:265-283.
121. Staud F, Pavek P. Breast cancer resistance protein (BCRP/ABCG2). Int J Biochem Cell Biol. 2005;37:720-725.
122. Mahdizadeh S, Karimi G, Behravan J, Arabzadeh S, Lage H, Kalalinia F. Crocin suppresses multidrug resistance in MRP overexpressing ovarian cancer cell line. Daru 2016;24:17.
123. Xia D. Ovarian cancer HO-8910 cell apoptosis induced by crocin in vitro. Nat Prod Commun 2015;10:249-252.
124. Min EK, Chong JU, Hwang HK, Pae SJ, Kang CM, Lee WJ. Negative oncologic impact of poor postoperative pain control in left-sided pancreatic cancer. World J Gastroenterol 2017;23:676-686.
125. Yar Saglam AS, Yilmaz A, Onen HI, Alp E, Kayhan H, Ekmekci A. HDAC inhibitors, MS-275 and salermide, potentiates the anticancer effect of EF24 in human pancreatic cancer cells. Excli J 2016;15:246-255.
126. Society AC. Cancer facts and figures 2013. American Cancer Society Atlanta; 2013.
127. Bakshi H, Sam S, Rozati R, Sultan P, Islam T, Rathore B, et al. DNA fragmentation and cell cycle arrest: a hallmark of apoptosis induced by crocin from kashmiri saffron in a human pancreatic cancer cell line. Asian Pac J Cancer Prev 2010;11:675-679.
128. Watanabe T, Kume K, Taip M, Shibata M, Kubo H, Ejiri Y, et al. Gastric mucosal cancer smaller than 7mm can be treated with conventional endoscopic mucosal resection as effectively as with endoscopic submucosal dissection. Hepatogastroenterology 2010;57:668-673.
129. Ang TL, Fock KM. Clinical epidemiology of gastric cancer. Singapore Med J 2014;55:621-628.
130. Hoshyar R, Bathaie SZ, Sadeghizadeh M. Crocin triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. DNA Cell Biol 2013;32:50-57.