Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells

Li,Sheng; Jiang,Sheng; Jiang,Wei; Zhou,Yue; Shen,Xiu‑Yin; Luo,Tao; Kong,Ling‑Ping; Wang,Hua‑Qiao

doi:10.3892/ol.2015.2869

Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells

Authors:
- Sheng Li
- Sheng Jiang
- Wei Jiang
- Yue Zhou
- Xiu‑Yin Shen
- Tao Luo
- Ling‑Ping Kong
- Hua‑Qiao Wang
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Affiliations: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: January 13, 2015 https://doi.org/10.3892/ol.2015.2869
Pages: 1254-1260

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Abstract

Crocetin is the main pharmacologically‑active component of saffron and has been considered as a promising candidate for cancer chemoprevention. The purpose of the present study was to investigate the anticancer effects of crocetin and the possible mechanisms of these properties in the esophageal squamous cell carcinoma cell line KYSE‑150. The KYSE‑150 cells were cultured in Dulbecco's modified Eagle's medium and incubated with 0, 12.5, 25, 50, 100 or 200 µmol/l crocetin for 48 h. Cell proliferation was measured using an MTT assay. Hoechst 33258 staining and observation under fluorescent microscopy were used to analyze the proapoptotic effects of crocetin. The migration rate was assessed by a wound‑healing assay. The cell cycle distribution was analyzed using flow cytometry analysis subsequent to propidium iodide staining. The expression of B-cell lymphoma-2-associated X protein (Bax) and cleaved caspase 3 was determined by western blot analysis. It was found that treatment of KYSE‑150 cells with crocetin for 48 h significantly inhibited the proliferation of the cells in a concentration‑dependent manner, and the inhibition of proliferation was associated with S phase arrest. Crocetin was also found to induce morphological changes and cell apoptosis in a dose‑dependent manner through increased expression of proapoptotic Bax and activated caspase 3. In addition, crocetin suppressed the migration of KYSE‑150 cells. The present study provides evidence that crocetin exerts a prominent chemopreventive effect against esophageal cancer through the inhibition of cell proliferation, migration and induction of apoptosis. These findings reveal that crocetin may be considered to be a promising future chemotherapeutic agent for esophageal cancer therapy.

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1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Cook MB, Chow WH and Devesa SS: Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. Br J Cancer. 101:855–859. 2009. View Article : Google Scholar : PubMed/NCBI
3	Szumiło J: Epidemiology and risk factors of the esophageal squamous cell carcinoma. Pol Merkur Lekarski. 26:82–85. 2009.(In Polish).
4	Rubenstein JH and Chen JW: Epidemiology of gastroesophageal reflux disease. Gastroenterol Clin North Am. 43:1–14. 2014. View Article : Google Scholar : PubMed/NCBI
5	Gaur P, Kim MP and Dunkin BJ: Esophageal cancer: Recent advances in screening, targeted therapy, and management. J Carcinog. 13:112014. View Article : Google Scholar : PubMed/NCBI
6	Smith TJ, Ryan LM, Douglass HO Jr, et al: Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys. 42:269–276. 1998. View Article : Google Scholar : PubMed/NCBI
7	Tepper J, Krasna MJ, Niedzwiecki D, et al: Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 26:1086–1092. 2008. View Article : Google Scholar : PubMed/NCBI
8	Blazeby JM, Farndon JR, Donovan J and Alderson D: A prospective longitudinal study examining the quality of life of patients with eso-phageal carcinoma. Cancer. 88:1781–1787. 2000. View Article : Google Scholar : PubMed/NCBI
9	Blazeby JM, Williams MH, Brookes ST, et al: Quality of life measurement in patients with oesophageal cancer. Gut. 37:505–508. 1995. View Article : Google Scholar : PubMed/NCBI
10	Kim T, Grobmyer SR, Smith R, et al: Esophageal cancer - the five year survivors. J Surg Oncol. 103:179–183. 2011. View Article : Google Scholar : PubMed/NCBI
11	Lin Y, Peng N, Li J, et al: Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase. Mol Cancer. 12:542013. View Article : Google Scholar : PubMed/NCBI
12	Wang L, Lu A, Meng F, et al: Inhibitory effects of lupeal acetate of Cortex periplocae on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Oncol Lett. 4:231–236. 2012.PubMed/NCBI
13	Rasul A, Yu B, Khan M, et al: Magnolol, a natural compound, induces apoptosis of SGC-7901 human gastric adenocarcinoma cells via themitochondrial and PI3K/Akt signaling pathways. Int J Oncol. 40:1153–1161. 2012.
14	Bolhassani A, Khavari A and Bathaie SZ: Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta. 1845:20–30. 2014.
15	Ordoudi SA, Befani CD, Nenadis N, et al: Further examination of antiradical properties of Crocus sativus stigmas extract rich in crocins. J Agric Food Chem. 57:3080–3086. 2009. View Article : Google Scholar : PubMed/NCBI
16	Higashino S, Sasaki Y, Giddings JC, et al: Crocetin, a carotenoid from Gardenia jasminoides Ellis, protects against hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Phytother Res. 28:1315–1319. 2014. View Article : Google Scholar : PubMed/NCBI
17	Tsantarliotou MP, Poutahidis T, Markala D, et al: Crocetin administration ameliorates endotoxin-induced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis. 24:305–310. 2013. View Article : Google Scholar : PubMed/NCBI
18	Nam KN, Park YM, Jung HJ, et al: Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol. 648:110–116. 2010. View Article : Google Scholar : PubMed/NCBI
19	Cai J, Yi FF, Bian ZY, et al: Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. J Cell Mol Med. 13:909–925. 2009. View Article : Google Scholar : PubMed/NCBI
20	Yang R, Vernon K, Thomas A, et al: Crocetin reduces activation of hepatic apoptotic pathways and improves survival in experimental hemorrhagic shock. JPEN J Parenter Enteral Nutr. 35:107–113. 2011. View Article : Google Scholar : PubMed/NCBI
21	Khan MB, Hoda MN, Ishrat T, et al: Neuroprotective efficacy of Nardostachys jatamansi and crocetin in conjunction with selenium in cognitive impairment. Neurol Sci. 33:1011–1020. 2012. View Article : Google Scholar
22	Bathaie SZ, Hoshyar R, Miri H and Sadeghizadeh M: Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer. Biochem Cell Biol. 91:397–403. 2013. View Article : Google Scholar : PubMed/NCBI
23	Li CY, Huang WF, Wang QL, et al: Crocetin induces cytotoxicity in colon cancer cells via p53-independent mechanisms. Asian Pac J Cancer Prev. 13:3757–3761. 2012. View Article : Google Scholar : PubMed/NCBI
24	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. 77:146–151. 2011. View Article : Google Scholar
25	Magesh V, DurgaBhavani K, Senthilnathan P, et al: In vivo protective effect of crocetin on benzo(a)pyrene-induced lung cancer in Swiss albino mice. Phytother Res. 23:533–539. 2009. View Article : Google Scholar
26	Song EL, Hou YP, Yu SP, et al: EFEMP1 expression promotes angiogenesis and accelerates the growth of cervical cancer in vivo. Gynecol Oncol. 121:174–180. 2011. View Article : Google Scholar
27	Gutheil WG, Reed G, Ray A, et al: Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol. 13:173–179. 2012. View Article : Google Scholar
28	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. 8:315–323. 2009. View Article : Google Scholar : PubMed/NCBI
29	Zhong YJ, Shi F, Zheng XL, et al: Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin. 32:1529–1536. 2011. View Article : Google Scholar : PubMed/NCBI
30	Nurse P: A long twentieth century of the cell cycle and beyond. Cell. 100:71–78. 2000. View Article : Google Scholar : PubMed/NCBI
31	Nurse P, Masui Y and Hartwell L: Understanding the cell cycle. Nat Med. 4:1103–1106. 1998. View Article : Google Scholar : PubMed/NCBI
32	Dehay C and Kennedy H: Cell-cycle control and cortical development. Nat Rev Neurosci. 8:438–450. 2007. View Article : Google Scholar : PubMed/NCBI
33	Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI
34	Chu G: Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J Biol Chem. 269:787–790. 1994.PubMed/NCBI
35	Warner TF: Apoptosis. Lancet. 2:12521972. View Article : Google Scholar : PubMed/NCBI
36	Wyllie AH: The biology of cell death in tumours. Anticancer Res. 5:131–136. 1985.PubMed/NCBI
37	Amin A, Hamza AA, Bajbouj K, et al: Saffron: a potential candidate for a novel anticancer drug against hepatocellular carcinoma. Hepatology. 54:857–867. 2011. View Article : Google Scholar : PubMed/NCBI
38	Luo X, Budihardjo I, Zou H, et al: Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 94:481–490. 1998. View Article : Google Scholar : PubMed/NCBI
39	Li P, Nijhawan D and Wang X: Mitochondrial activation of apoptosis. Cell. 116(Suppl 2): S57–S59. 2004. View Article : Google Scholar : PubMed/NCBI
40	Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI
41	Napier KJ, Scheerer M and Misra S: Esophageal cancer: A review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 6:112–120. 2014. View Article : Google Scholar : PubMed/NCBI
42	Javle M, Ailawadhi S, Yang GY, et al: Palliation of malignant dysphagia in esophageal cancer: a literature-based review. J Support Oncol. 4:365–373. 3792006.PubMed/NCBI
43	Martin TA: The role of tight junctions in cancer metastasis. Semin Cell Dev Biol. 36C:224–231. 2014. View Article : Google Scholar
44	Liotta LA, Rao CN and Barsky SH: Tumor invasion and the extracellular matrix. Lab Invest. 49:636–649. 1983.PubMed/NCBI
45	Mahadevan V and Hart IR: Metastasis and angiogenesis. Acta Oncol. 29:97–103. 1990. View Article : Google Scholar : PubMed/NCBI
46	Xiang M, Qian ZY, Zhou CH, et al: Crocetin inhibits leukocyte adherence to vascular endothelial cells induced by AGEs. J Ethnopharmacol. 107:25–31. 2006. View Article : Google Scholar : PubMed/NCBI
47	Umigai N, Tanaka J, Tsuruma K, et al: Crocetin, a carotenoid derivative, inhibits VEGF-induced angiogenesis via suppression of p38 phosphorylation. Curr Neurovasc Res. 9:102–109. 2012. View Article : Google Scholar : PubMed/NCBI