Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

Crocin Potentiates Anti-tumor Properties of 5-FU by Regulating Cell Proliferation and Tumor Necrosis in Breast Cancer

Author(s): Nastaran Rezaei, Abdulridha Mohammed Al-Asady, Milad Hashemzehi, Maryam Moradi Binabaj, Farzad Rahmani, Amir Avan, Moein Eskandari, Mohammad Jalili-Nik, Fereshteh Asgharzadeh, Seyedeh Elnaz Nazari, Mikhail Ryzhikov, Majid Khazaei* and Seyed Mahdi Hassanian*

Volume 21, Issue 15, 2024

Published on: 23 January, 2024

Page: [3161 - 3168] Pages: 8

DOI: 10.2174/0115701808258032231204080133

Price: $65

Abstract

Introduction: Breast cancer is one of the most prevalent malignancies among women around the world. Crocus sativus, a natural food coloring and flavoring, has potent anti-tumor properties. The aim of the current study was to investigate the therapeutic potential of crocin, the main pharmacological active component of saffron, either alone or in combination with the standard chemotherapeutic treatment, 5-FU, in Breast cancer (BC) progression in both cellular and animal models.

Material and Methods: MTT, Real-Time PCR, Western Blotting, Hematoxylin and eosin (H&E) tissue staining were applied to determine the anti-tumor properties of crocin in in vitro and in vivo samples.

Results: Our findings showed that crocin decreased breast cancer cell proliferation by suppressing cyclin D1 expression and Wnt/β-catenin signaling activation. Moreover, this molecule improved 5- FU anti-cancer activities by decreasing the tumor volume and weight, increasing tumor necrosis, and suppressing tumor inflammation in an animal model. Inflammation-associated anti-cancer activity of crocin is mediated by the down-regulation of pro-inflammatory genes, including IFN-γ and IL-1β, as well as inhibition of oxidative stress responses within the tumor environment.

Conclusion: This is the first study demonstrating the potent anti-tumor properties of crocin against BC progression. Our results suggest that this effective and low-toxic molecule could be a promising agent for reducing BC tumor progression when administered either alone or in combination with standard treatment in breast cancer patients.

« Previous Next »
[1]
Benson, J.R.; Jatoi, I. The global breast cancer burden. Future Oncol., 2012, 8(6), 697-702.
[http://dx.doi.org/10.2217/fon.12.61] [PMID: 22764767]
[2]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[3]
Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin., 2016, 66(4), 271-289.
[http://dx.doi.org/10.3322/caac.21349] [PMID: 27253694]
[4]
Afolabi, O.K.; Adeleke, G.E.; Ugbaja, R.N. Crocin alleviates 5-Fluorouracil-induced hepatotoxicity through the abrogation of oxidative stress in male wistar rats. Asian Pacific Journal of Health Sciences, 2016, 3(2), 58-68.
[http://dx.doi.org/10.21276/apjhs.2016.3.2.11]
[5]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[6]
Swain, S.M.; Lippman, M.E.; Egan, E.F.; Drake, J.C.; Steinberg, S.M.; Allegra, C.J. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J. Clin. Oncol., 1989, 7(7), 890-899.
[http://dx.doi.org/10.1200/JCO.1989.7.7.890] [PMID: 2661735]
[7]
Raymond, E.; Buquet-Fagot, C.; Djelloul, S.; Mester, J.; Cvitkovic, E.; Allain, P.; Louvet, C.; Gespach, C. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs, 1997, 8(9), 876-885.
[http://dx.doi.org/10.1097/00001813-199710000-00009] [PMID: 9402315]
[8]
González-Sarrías, A.; Tomé-Carneiro, J.; Bellesia, A.; Tomás-Barberán, F.A.; Espín, J.C. The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells. Food Funct., 2015, 6(5), 1460-1469.
[http://dx.doi.org/10.1039/C5FO00120J] [PMID: 25857357]
[9]
Ko, E.Y.; Moon, A. Natural products for chemoprevention of breast cancer. J. Cancer Prev., 2015, 20(4), 223-231.
[http://dx.doi.org/10.15430/JCP.2015.20.4.223] [PMID: 26734584]
[10]
Goldberg, J.E.; Schwertfeger, K.L. Proinflammatory cytokines in breast cancer: Mechanisms of action and potential targets for therapeutics. Curr. Drug Targets, 2010, 11(9), 1133-1146.
[http://dx.doi.org/10.2174/138945010792006799] [PMID: 20545607]
[11]
Amin, K.A.; Mohamed, B.M.; El-wakil, M.A.M.; Ibrahem, S.O. Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers. J. Breast Cancer, 2012, 15(3), 306-312.
[http://dx.doi.org/10.4048/jbc.2012.15.3.306] [PMID: 23091543]
[12]
Amerizadeh, F.; Rezaei, N.; Rahmani, F.; Hassanian, S.M.; Moradi-Marjaneh, R.; Fiuji, H.; Boroumand, N.; Nosrati-Tirkani, A.; Ghayour-Mobarhan, M.; Ferns, G.A.; Khazaei, M.; Avan, A. Crocin synergistically enhances the antiproliferative activity of 5‐flurouracil through Wnt/PI3K pathway in a mouse model of colitis‐associated colorectal cancer. J. Cell. Biochem., 2018, 119(12), 10250-10261.
[http://dx.doi.org/10.1002/jcb.27367] [PMID: 30129057]
[13]
Wang, J.; Ke, Y.; Shu, T. Crocin has pharmacological effects against the pathological behavior of colon cancer cells by interacting with the STAT3 signaling pathway. Exp. Ther. Med., 2020, 19(2), 1297-1303.
[PMID: 32010302]
[14]
Yao, C.; Liu, B.B.; Qian, X.D.; Li, L.Q.; Cao, H.B.; Guo, Q.S.; Zhou, G.F. Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity. OncoTargets Ther., 2018, 11, 2017-2028.
[http://dx.doi.org/10.2147/OTT.S154586] [PMID: 29670377]
[15]
Chen, S.; Zhao, S.; Wang, X.; Zhang, L.; Jiang, E.; Gu, Y.; Shangguan, A.J.; Zhao, H.; Lv, T.; Yu, Z. Crocin inhibits cell proliferation and enhances cisplatin and pemetrexed chemosensitivity in lung cancer cells. Transl. Lung Cancer Res., 2015, 4(6), 775-783.
[PMID: 26798587]
[16]
Hashemzehi, M.; Rahmani, F.; Khoshakhlagh, M.; Avan, A.; Asgharzadeh, F.; Barneh, F.; Moradi-Marjaneh, R.; Soleimani, A.; Fiuji, H.; Ferns, G.A.; Ryzhikov, M.; Jafari, M.; Khazaei, M.; Hassanian, S.M. Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. EXCLI J., 2021, 20, 506-521.
[PMID: 33883980]
[17]
Li, B.; Ryder, J.; Su, Y.; Zhou, Y.; Liu, F.; Ni, B. FRAT1 peptide decreases Aβ production in swAPP 751 cells. FEBS Lett., 2003, 553(3), 347-350.
[http://dx.doi.org/10.1016/S0014-5793(03)01042-1] [PMID: 14572648]
[18]
Cross, D.A.E.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995, 378(6559), 785-789.
[http://dx.doi.org/10.1038/378785a0] [PMID: 8524413]
[19]
Vigneron, F.; Dos Santos, P.; Lemoine, S.; Bonnet, M.; Tariosse, L.; Couffinhal, T.; Duplaà, C.; Jaspard-Vinassa, B. GSK-3β at the crossroads in the signalling of heart preconditioning: implication of mTOR and Wnt pathways. Cardiovasc. Res., 2011, 90(1), 49-56.
[http://dx.doi.org/10.1093/cvr/cvr002] [PMID: 21233250]
[20]
Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3), 469-480.
[http://dx.doi.org/10.1016/j.cell.2006.10.018] [PMID: 17081971]
[21]
Behrens, J.; von Kries, J.P.; Kühl, M.; Bruhn, L.; Wedlich, D.; Grosschedl, R.; Birchmeier, W. Functional interaction of β-catenin with the transcription factor LEF-1. Nature, 1996, 382(6592), 638-642.
[http://dx.doi.org/10.1038/382638a0] [PMID: 8757136]
[22]
Aung, H.H.; Wang, C.Z.; Ni, M.; Fishbein, A.; Mehendale, S.R.; Xie, J.T.; Shoyama, C.Y.; Yuan, C.S. Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp. Oncol., 2007, 29(3), 175-180.
[PMID: 18004240]
[23]
Arzi, L.; Farahi, A.; Jafarzadeh, N.; Riazi, G.; Sadeghizadeh, M.; Hoshyar, R. Inhibitory effect of crocin on metastasis of triple-negative breast cancer by interfering with Wnt/β-Catenin pathway in murine model. DNA Cell Biol., 2018, 37(12), 1068-1075.
[http://dx.doi.org/10.1089/dna.2018.4351] [PMID: 30351203]
[24]
Liu, H.; Wang, G.; Yang, L.; Qu, J.; Yang, Z.; Zhou, X. Knockdown of long non-coding RNA UCA1 increases the tamoxifen sensitivity of breast cancer cells through inhibition of Wnt/β-catenin pathway. PLoS One, 2016, 11(12), e0168406.
[http://dx.doi.org/10.1371/journal.pone.0168406] [PMID: 27977766]
[25]
Chikazawa, N.; Tanaka, H.; Tasaka, T.; Nakamura, M.; Tanaka, M.; Onishi, H.; Katano, M. Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells. Anticancer Res., 2010, 30(6), 2041-2048.
[PMID: 20651349]
[26]
Wang, Z.; Li, B.; Zhou, L.; Yu, S.; Su, Z.; Song, J.; Sun, Q.; Sha, O.; Wang, X.; Jiang, W.; Willert, K.; Wei, L.; Carson, D.A.; Lu, D. Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proc. Natl. Acad. Sci. USA, 2016, 113(46), 13150-13155.
[http://dx.doi.org/10.1073/pnas.1616336113] [PMID: 27799526]
[27]
Takahashi-Yanaga, F.; Sasaguri, T. Drug development targeting the glycogen synthase kinase-3β (GSK-3β)-mediated signal transduction pathway: inhibitors of the Wnt/β-catenin signaling pathway as novel anticancer drugs. J. Pharmacol. Sci., 2009, 109(2), 179-183.
[http://dx.doi.org/10.1254/jphs.08R28FM] [PMID: 19179804]
[28]
Dey, N.; Barwick, B.G.; Moreno, C.S.; Ordanic-Kodani, M.; Chen, Z.; Oprea-Ilies, G.; Tang, W.; Catzavelos, C.; Kerstann, K.F.; Sledge, G.W., Jr; Abramovitz, M.; Bouzyk, M.; De, P.; Leyland-Jones, B.R. Wnt signaling in triple negative breast cancer is associated with metastasis. BMC Cancer, 2013, 13(1), 537.
[http://dx.doi.org/10.1186/1471-2407-13-537] [PMID: 24209998]
[29]
Arzi, L.; Riazi, G.; Sadeghizadeh, M.; Hoshyar, R.; Jafarzadeh, N. A comparative study on anti-invasion, antimigration, and antiadhesion effects of the bioactive carotenoids of saffron on 4T1 breast cancer cells through their effects on Wnt/β-catenin pathway genes. DNA Cell Biol., 2018, 37(8), 697-707.
[http://dx.doi.org/10.1089/dna.2018.4248] [PMID: 29969282]
[30]
Phesse, T.; Flanagan, D.; Vincan, E. Frizzled7: A promising Achilles’ heel for targeting the Wnt receptor complex to treat cancer. Cancers, 2016, 8(5), 50.
[http://dx.doi.org/10.3390/cancers8050050] [PMID: 27196929]
[31]
Yang, L.; Wu, X.; Wang, Y.; Zhang, K.; Wu, J.; Yuan, Y-C.; Deng, X.; Chen, L.; Kim, C.C.H.; Lau, S.; Somlo, G.; Yen, Y. FZD7 has a critical role in cell proliferation in triple negative breast cancer. Oncogene, 2011, 30(43), 4437-4446.
[http://dx.doi.org/10.1038/onc.2011.145] [PMID: 21532620]
[32]
Chang, J.X.; Gao, F.; Zhao, G.Q.; Zhang, G.J. Expression and clinical significance of NEDD9 in lung tissues. Med. Oncol., 2012, 29(4), 2654-2660.
[http://dx.doi.org/10.1007/s12032-012-0213-0] [PMID: 22447485]
[33]
Li, Y.; Bavarva, J.H.; Wang, Z.; Guo, J.; Qian, C.; Thibodeau, S.N.; Golemis, E.A.; Liu, W. HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression. Oncogene, 2011, 30(23), 2633-2643.
[http://dx.doi.org/10.1038/onc.2010.632] [PMID: 21317929]
[34]
Kong, C.; Wang, C.; Wang, L.; Ma, M.; Niu, C.; Sun, X.; Du, J.; Dong, Z.; Zhu, S.; Lu, J.; Huang, B. NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer. PLoS One, 2011, 6(7), e22666.
[http://dx.doi.org/10.1371/journal.pone.0022666] [PMID: 21829474]
[35]
Gilles, C.; Polette, M.; Mestdagt, M.; Nawrocki-Raby, B.; Ruggeri, P.; Birembaut, P.; Foidart, J.M. Transactivation of vimentin by β-catenin in human breast cancer cells. Cancer Res., 2003, 63(10), 2658-2664.
[PMID: 12750294]
[36]
Olsen, J.J.; Pohl, S.Ö-G.; Deshmukh, A.; Visweswaran, M.; Ward, N.C.; Arfuso, F.; Agostino, M.; Dharmarajan, A. The role of Wnt signalling in angiogenesis. Clin. Biochem. Rev., 2017, 38(3), 131-142.
[PMID: 29332977]
[37]
Lehmann, B.D.; Bauer, J.A.; Chen, X.; Sanders, M.E.; Chakravarthy, A.B.; Shyr, Y.; Pietenpol, J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest., 2011, 121(7), 2750-2767.
[http://dx.doi.org/10.1172/JCI45014] [PMID: 21633166]
[38]
Crampton, S.P.; Wu, B.; Park, E.J.; Kim, J.H.; Solomon, C.; Waterman, M.L.; Hughes, C.C.W. Integration of the β-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. PLoS One, 2009, 4(11), e7841.
[http://dx.doi.org/10.1371/journal.pone.0007841] [PMID: 19924227]
[39]
Mehner, C.; Hockla, A.; Miller, E.; Ran, S.; Radisky, D.C.; Radisky, E.S. Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget, 2014, 5(9), 2736-2749.
[http://dx.doi.org/10.18632/oncotarget.1932] [PMID: 24811362]
[40]
Deng, Y.H.; Pu, X.X.; Huang, M.J.; Xiao, J.; Zhou, J.M.; Lin, T.Y.; Lin, E.H. 5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells. Chin. J. Cancer, 2010, 29(9), 810-815.
[http://dx.doi.org/10.5732/cjc.010.10134] [PMID: 20800023]
[41]
Morris, P.G.; Hudis, C.; Giri, D.D.; Morrow, M.; Falcone, D.J.; Zhou, X.K. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev. Res., 2011, 4(7), 1021-1029.
[http://dx.doi.org/10.1158/1940-6207.CAPR-11-0110]
[42]
Calogero, R.A.; Cordero, F.; Forni, G.; Cavallo, F. Inflammation and breast cancer. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice. Breast Cancer Res., 2007, 9(4), 211.
[http://dx.doi.org/10.1186/bcr1745] [PMID: 17705881]
[43]
Bakshi, H.A.; Hakkim, F.L.; Sam, S.; Javid, F.; Rashan, L. Dietary crocin reverses melanoma metastasis. J. Biomed. Res., 2017, 32(1), 39-50.
[PMID: 29219852]
[44]
Sosnoski, D.M.; Norgard, R.J.; Grove, C.D.; Foster, S.J.; Mastro, A.M. Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment. Clin. Exp. Metastasis, 2015, 32(4), 335-344.
[http://dx.doi.org/10.1007/s10585-015-9710-9] [PMID: 25749879]
[45]
Mandai, M.; Hamanishi, J.; Abiko, K.; Matsumura, N.; Baba, T.; Konishi, I. Dual faces of IFNγ in cancer progression: A role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin. Cancer Res., 2016, 22(10), 2329-2334.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0224] [PMID: 27016309]
[46]
Hajra, K.M.; Chen, D.Y.; Fearon, E.R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res., 2002, 62(6), 1613-1618.
[PMID: 11912130]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy