Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Quercetin Promotes Cell Cycle Arrest and Apoptosis and Attenuates the Proliferation of Human Chronic Myeloid Leukemia Cell Line-K562 Through Interaction with HSPs (70 and 90), MAT2A and FOXM1

Author(s): Ali Hassanzadeh, Elham Hosseinzadeh, Saleheh Rezapour, Ghasem Vahedi, Navideh Haghnavaz and Faroogh Marofi*

Volume 19 , Issue 12 , 2019

Page: [1523 - 1534] Pages: 12

DOI: 10.2174/1871520619666190729150442

Price: $65


Background: Chronic Myeloid Leukaemia (CML) starts in certain blood-forming cells of the bone marrow when cells acquire Philadelphia chromosome. Nowadays, scientists attempt to find novel and safe therapeutic agents and approaches for CML therapy using Tyrosine Kinase Inhibitors (TKIs), CML conventional treatment agents, has some restrictions and also adverse effects. Recently, it has been proposed that phytochemicals, such as flavonoids due to their low side effects and notable safety have the potential to be used for CML therapy.

Materials and Methods: K-562 cells were exposed with three concentrations of the querectin (10, 40 and 80µM) for 12, 24 and 48 hours. After that, these cells apoptosis rate was estimated using Annexin-V/PI staining and flowcytometry analysis, and their proliferation rate was evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT). Finally, the expression of the 70 and 90 kilodalton heat shock proteins (HSP70 and 90), methionine adenosyltransferase 2A (MAT2A), Forkhead box protein M1 (FOXM1), caspase-3 and -8, Bcl-X(L) and Bax involved in leukemic cells survival and proliferation was assessed using Real-Time PCR within 12, 24 and 48 hours after exposure with quercetin 40 and 80µM.

Results: Considering consequences, querecetin induced apoptosis in K-562 cells, and also abrogated these cells proliferation. On the other hand, RT-PCR results showed a reduction in some of the candidate genes expression, especially HSP70, Bcl-X(L) and FOXM1, when cells were treated with quercetin 40 and 80µM. Also, Bax, caspase-3 and caspase-8 expression was significantly improved in K-562 cells upon quercetin exposure.

Conclusion: We concluded that CML therapy by querecetin due to its anti-proliferative and anti-survival potentials could lead to the promising therapeutic outcome through targeting major survival and proliferation involved genes expression.

Keywords: Chronic myeloid leukaemia (CML), K-562, quercetin, apoptosis, proliferation, HSP.

Graphical Abstract
Salesse, S.; Verfaillie, C.M. BCR/ABL: From molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene, 2002, 21(56), 8547-8559.
[] [PMID: 12476301]
De Carvalho, D.D.; Binato, R.; Pereira, W.O.; Leroy, J.M.; Colassanti, M.D.; Proto-Siqueira, R.; Bueno-Da-Silva, A.E.; Zago, M.A.; Zanichelli, M.A.; Abdelhay, E.; Castro, F.A.; Jacysyn, J.F.; Amarante-Mendes, G.P. BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients. Oncogene, 2011, 30(2), 223-233.
[] [PMID: 20838376]
Chen, Y.; Wang, T.; Du, J.; Li, Y.; Wang, X.; Zhou, Y. The critical role of PTEN/PI3K/AKT signaling pathway in shikonin-induced apoptosis and proliferation inhibition of chronic myeloid leukemia. Cell. Physiol. Biochem.: Int. J. Experim. Cell. Physiol. Biochem. Pharmacol., 2018, 47(3), 981-993.
Huang, R.; Liu, H.; Chen, Y.; He, Y.; Kang, Q.; Tu, S.; He, Y.; Zhou, X.; Wang, L.; Yang, J.; Wu, A.; Li, Y. EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway. Oncol. Rep., 2018, 39(1), 119-128.
[PMID: 29192326]
Frazer, R.; Irvine, A.E.; McMullin, M.F. Chronic myeloid leukaemia in the 21st Century. Ulster Med. J., 2007, 76(1), 8-17.
[PMID: 17288299]
Bhatia, R. Novel approaches to therapy in CML. Hematology (Am. Soc. Hematol. Educ. Program), 2017, 2017(1), 115-120.
[] [PMID: 29222245]
Mahon, F.X. Treatment-free remission in CML: Who, how, and why? Hematology (Am. Soc. Hematol. Educ. Program), 2017, 2017(1), 102-109.
[] [PMID: 29222243]
Abruzzese, E.; Trawinska, M.M.; de Fabritiis, P.; Baccarani, M. Management of pregnant chronic myeloid leukemia patients. Expert Rev. Hematol., 2016, 9(8), 781-791.
[] [PMID: 27352939]
Hartmann, J.T.; Haap, M.; Kopp, H.G.; Lipp, H.P. Tyrosine kinase inhibitors - A review on pharmacology, metabolism and side effects. Curr. Drug Metab., 2009, 10(5), 470-481.
[] [PMID: 19689244]
Caldemeyer, L.; Dugan, M.; Edwards, J.; Akard, L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr. Hematol. Malig. Rep., 2016, 11(2), 71-79.
[] [PMID: 26922746]
Talati, C.; Pinilla-Ibarz, J. Resistance in chronic myeloid leukemia: Definitions and novel therapeutic agents. Curr. Opin. Hematol., 2018, 25(2), 154-161.
[PMID: 29266016]
Inoue, A.; Kobayashi, C.I.; Shinohara, H.; Miyamoto, K.; Yamauchi, N.; Yuda, J.; Akao, Y.; Minami, Y. Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence. Int. J. Hematol., 2018, 108(4), 365-370.
[] [PMID: 30155588]
Tari Ashizawa, A.; Ohanian, M.; Cortes, J.E. BP1001, a novel therapeutic for chronic myelogenous leukemia. Blood, 2016, 128(22), 4239.
Saraei, R.; Marofi, F.; Naimi, A.; Talebi, M.; Ghaebi, M.; Javan, N. Leukemia therapy by flavonoids: Future and involved mechanisms. J. Cell. Physiol., 2019, 234(6), 8203-8220.
[PMID: 30500074]
Bartmańska, A.; Tronina, T.; Popłoński, J.; Milczarek, M.; Filip-Psurska, B.; Wietrzyk, J. Highly cancer selective antiproliferative activity of natural prenylated flavonoids. Molecules, 2018, 23(11)E2922
[] [PMID: 30423918]
Benavente-García, O.; Castillo, J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. J. Agric. Food Chem., 2008, 56(15), 6185-6205.
[] [PMID: 18593176]
Busch, C.; Burkard, M.; Leischner, C.; Lauer, U.M.; Frank, J.; Venturelli, S. Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clin. Epigenetics, 2015, 7(1), 64.
[] [PMID: 26161152]
Dekant, W.; Fujii, K.; Shibata, E.; Morita, O.; Shimotoyodome, A. Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements. Toxicol. Lett., 2017, 277, 104-108.
[] [PMID: 28655517]
Grosso, G. Effects of polyphenol-rich foods on human health. Nutrients, 2018, 10(8)E1089
[] [PMID: 30110959]
Solmaz, S.; Adan Gokbulut, A.; Cincin, B.; Ozdogu, H.; Boga, C.; Cakmakoglu, B.; Kozanoglu, I.; Baran, Y. Therapeutic potential of apigenin, a plant flavonoid, for imatinib-sensitive and resistant chronic myeloid leukemia cells. Nutr. Cancer, 2014, 66(4), 599-612.
[] [PMID: 24669768]
Liu, Y.L.; Tang, L.H.; Liang, Z.Q.; You, B.G.; Yang, S.L. Growth inhibitory and apoptosis inducing by effects of total flavonoids from Lysimachia clethroides Duby in human chronic myeloid leukemia K562 cells. J. Ethnopharmacol., 2010, 131(1), 1-9.
[] [PMID: 20420897]
Klikova, K.; Pilchova, I.; Stefanikova, A.; Hatok, J.; Dobrota, D.; Racay, P. The Role of Heat Shock Proteins in Leukemia. Klin. Onkol., 2016, 29(1), 29-38.
Khan, I.; Halasi, M.; Patel, A.; Schultz, R.; Kalakota, N.; Chen, Y.H.; Aardsma, N.; Liu, L.; Crispino, J.D.; Mahmud, N.; Frankfurt, O.; Gartel, A.L. FOXM1 contributes to treatment failure in acute myeloid leukemia. JCI Insight, 2018, 3(15)121583
[] [PMID: 30089730]
Halim, A.B.; LeGros, H.L., Jr; Chamberlin, M.E.; Geller, A.; Kotb, M. Distinct patterns of protein binding to the MAT2A promoter in normal and leukemic T cells. Biochim. Biophys. Acta, 2001, 1540(1), 32-42.
[] [PMID: 11476892]
Steiner, K.; Graf, M.; Hecht, K.; Reif, S.; Rossbacher, L.; Pfister, K.; Kolb, H.J.; Schmetzer, H.M.; Multhoff, G. High HSP70-membrane expression on leukemic cells from patients with acute myeloid leukemia is associated with a worse prognosis. Leukemia, 2006, 20(11), 2076-2079.
[] [PMID: 16990768]
Khajapeer, K.V.; Baskaran, R. Hsp90 inhibitors for the treatment of chronic myeloid leukemia. Leukemia Res. Treat., 2015, 2015757694
[] [PMID: 26770832]
Nakamura, S.; Hirano, I.; Okinaka, K.; Takemura, T.; Yokota, D.; Ono, T.; Shigeno, K.; Shibata, K.; Fujisawa, S.; Ohnishi, K. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis, 2010, 31(11), 2012-2021.
[] [PMID: 20823107]
Mancini, M.; Castagnetti, F.; Soverini, S.; Leo, E.; De Benedittis, C.; Gugliotta, G.; Rosti, G.; Bavaro, L.; De Santis, S.; Monaldi, C.; Martelli, M.; Santucci, M.A.; Cavo, M.; Martinelli, G. FOXM1 transcription factor: A new component of chronic myeloid leukemia stem cell proliferation advantage. J. Cell. Biochem., 2017, 118(11), 3968-3975.
[] [PMID: 28401599]
Cheng, S.; Gao, N.; Zhang, Z.; Chen, G.; Budhraja, A.; Ke, Z. Quercetin induces tumor-selective apoptosis through downregulation of Mcl-1 and activation of Bax. Off. J. Am. Assoc. Cancer Res., 2010, 16(23), 5679-5691.
Gokbulut, A.A.; Apohan, E.; Baran, Y. Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest. Hematology, 2013, 18(3), 144-150.
[] [PMID: 23432965]
Narra, R.K.; Flynn, K.E.; Atallah, E. Chronic myeloid leukemia-the promise of tyrosine kinase inhibitor discontinuation. Curr. Hematol. Malig. Rep., 2017, 12(5), 415-423.
[] [PMID: 28944397]
Yu, L.; Wang, H.B.; Jiang, Q. Patient reported outcome of tyrosine kinase inhibitor related side effects and their impact on daily life in Chinese patients with chronic myeloid leukemia in the chronic phase. Zhonghua Xue Ye Xue Za Zhi = Zhonghua xueyexue zazhi,, 2016, 37(11), 929-935.
Deremer, D.L.; Ustun, C.; Natarajan, K. Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin. Ther., 2008, 30(11), 1956-1975.
[] [PMID: 19108785]
Cassidy, A.; Huang, T.; Rice, M.S.; Rimm, E.B.; Tworoger, S.S. Intake of dietary flavonoids and risk of epithelial ovarian cancer. Am. J. Clin. Nutr., 2014, 100(5), 1344-1351.
[] [PMID: 25332332]
Lagiou, P.; Rossi, M.; Lagiou, A.; Tzonou, A.; La Vecchia, C.; Trichopoulos, D. Flavonoid intake and liver cancer: A case-control study in Greece. Cancer Causes Control, 2008, 19(8), 813-818.
[] [PMID: 18350370]
Woo, S.M.; Choi, Y.K.; Kim, A.J.; Cho, S.G.; Ko, S.G. p53 causes buteinmediated apoptosis of chronic myeloid leukemia cells. Mol. Med. Rep., 2016, 13(2), 1091-1096.
[] [PMID: 26676515]
Tsai, T.C.; Huang, H.P.; Chang, K.T.; Wang, C.J.; Chang, Y.C. Anthocyanins from roselle extract arrest cell cycle G2/M phase transition via ATM/Chk pathway in p53-deficient leukemia HL-60 cells. Environ. Toxicol., 2017, 32(4), 1290-1304.
[] [PMID: 27444805]
Adan, A.; Baran, Y. Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumour Biol., 2016, 37(5), 5781-5795.
[] [PMID: 26408178]
Burmistrova, O.; Marrero, M.T.; Estévez, S.; Welsch, I.; Brouard, I.; Quintana, J.; Estévez, F. Synthesis and effects on cell viability of flavonols and 3-methyl ether derivatives on human leukemia cells. Eur. J. Med. Chem., 2014, 84, 30-41.
[] [PMID: 25014747]
Maso, V.; Calgarotto, A.K.; Franchi, G.C., Jr; Nowill, A.E.; Filho, P.L.; Vassallo, J.; Saad, S.T. Multitarget effects of quercetin in leukemia. Cancer Prev. Res. (Phila.), 2014, 7(12), 1240-1250.
[] [PMID: 25293876]
Chen, X.; Dong, X.S.; Gao, H.Y.; Jiang, Y.F.; Jin, Y.L.; Chang, Y.Y.; Chen, L.Y.; Wang, J.H. Suppression of HSP27 increases the antitumor effects of quercetin in human leukemia U937 cells. Mol. Med. Rep., 2016, 13(1), 689-696.
[] [PMID: 26648539]
Lu, H.Y.; Chen, J.; Du, S.H.; Jia, P.M.; Tong, J.H.; Wu, Y.L.; Zhou, L. Effects of quercetin on chronic myeloid leukemia cell line resistant to imatinib and its mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2017, 25(2), 346-352.
[PMID: 28446273]
Russo, M.; Milito, A.; Spagnuolo, C.; Carbone, V.; Rosén, A.; Minasi, P.; Lauria, F.; Russo, G.L. CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia. Oncotarget, 2017, 8(26), 42571-42587.
[] [PMID: 28489572]
Mutlu Altundağ, E.; Yılmaz, A.M.; Koçtürk, S.; Taga, Y.; Yalçın, A.S. Synergistic induction of apoptosis by quercetin and curcumin in chronic myeloid leukemia (K562) cells. Nutr. Cancer, 2018, 70(1), 97-108.
[] [PMID: 29161179]
He, D.; Guo, X.; Zhang, E.; Zi, F.; Chen, J.; Chen, Q.; Lin, X.; Yang, L.; Li, Y.; Wu, W.; Yang, Y.; He, J.; Cai, Z. Quercetin induces cell apoptosis of myeloma and displays a synergistic effect with dexamethasone in vitro and in vivo xenograft models. Oncotarget, 2016, 7(29), 45489-45499.
[] [PMID: 27329589]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy