Cellular and molecular alterations induced by low‑dose fisetin in human chronic myeloid leukemia cells

Klimaszewska‑Wiśniewska,Anna; Grzanka,Dariusz; Czajkowska,Paulina; Hałas‑Wiśniewska,Marta; Durślewicz,Justyna; Antosik,Paulina; Grzanka,Alina; Gagat,Maciej

doi:10.3892/ijo.2019.4889

Cellular and molecular alterations induced by low‑dose fisetin in human chronic myeloid leukemia cells

Authors:
- Anna Klimaszewska‑Wiśniewska
- Dariusz Grzanka
- Paulina Czajkowska
- Marta Hałas‑Wiśniewska
- Justyna Durślewicz
- Paulina Antosik
- Alina Grzanka
- Maciej Gagat
View Affiliations

Affiliations: Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85‑092 Bydgoszcz, Poland, Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85‑092 Bydgoszcz, Poland
Published online on: October 2, 2019 https://doi.org/10.3892/ijo.2019.4889
Pages: 1261-1274
Copyright: © Klimaszewska‑Wiśniewska et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to evaluate the cellular and molecular effects of low concentrations of the flavonoid, fisetin, on K562 human chronic myeloid leukemia cells, in the context of both potential anti‑proliferative and anti‑metastatic effects. Thiazolyl blue tetrazolium bromide assay, Trypan blue exclusion assay, Annexin V/propidium iodide test, cell cycle analysis, Transwell migration and invasion assays, the fluorescence staining of β‑catenin and F‑actin as well as reverse transcription‑quantitative polymerase chain reaction were performed to achieve the research goal. Furthermore, the nature of the interaction between fisetin and arsenic trioxide in the K562 cells was analyzed according to the Chou‑Talalay median‑effect method. We found that low concentrations of fisetin had not only a negligible effect on the viability and apoptosis of the K562 cells, but also modulated the mRNA levels of selected metastatic‑related markers, accompanied by an increase in the migratory and invasive properties of these cancer cells. Although some markers of cell death were significantly elevated in response to fisetin treatment, these were counterbalanced through anti‑apoptotic and pro‑survival signals. With decreasing concentrations of fisetin and arsenic trioxide, the antagonistic interactions between the 2 agents increased. On the whole, the findings of this study suggest that careful consideration should be taken when advising cancer patients to take fisetin as a dietary supplement and when considering fisetin as a potential candidate for the treatment of chronic myeloid leukemia. Further more detailed studies are required to confirm our findings.

View Figures

View References

1	Thomasset SC, Berry DP, Garcea G, Marczylo T, Steward WP and Gescher AJ: Dietary polyphenolic phytochemicals-promising cancer chemopreventive agents in humans? A review of their clinical properties. Int J Cancer. 120:451–458. 2007. View Article : Google Scholar
2	Ramos S: Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways. Mol Nutr Food Res. 52:507–526. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sak K: Chemotherapy and dietary phytochemical agents. Chemother Res Pract. 2012:2825702012.
4	Surh YJ: Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 3:768–780. 2003. View Article : Google Scholar : PubMed/NCBI
5	Jash SK and Mondal S: Bioactive flavonoid fisetin-a molecule of pharmacological interest. J Org Biomol Chem. 2:89–128. 2014.
6	Liu XF, Long HJ, Miao XY, Liu GL and Yao HL: Fisetin inhibits liver cancer growth in a mouse model: Relation to dopamine receptor. Oncol Rep. 38:53–62. 2017. View Article : Google Scholar : PubMed/NCBI
7	Khan N, Asim M, Afaq F, Abu Zaid M and Mukhtar H: A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res. 68:8555–8563. 2008. View Article : Google Scholar : PubMed/NCBI
8	Khan N, Syed DN, Ahmad N and Mukhtar H: Fisetin: A dietary antioxidant for health promotion. Antioxid Redox Signal. 19:151–162. 2013. View Article : Google Scholar :
9	Syed DN, Adhami VM, Khan N, Khan MI and Mukhtar H: Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol. 40-41:130–140. 2016. View Article : Google Scholar : PubMed/NCBI
10	Mukhtar E, Adhami VM, Sechi M and Mukhtar H: Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett. 367:173–183. 2015. View Article : Google Scholar : PubMed/NCBI
11	Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH and Mukhtar H: Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 31:1424–1433. 2010. View Article : Google Scholar : PubMed/NCBI
12	Jia S, Xu X, Zhou S, Chen Y, Ding G and Cao L: Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress-and mitochondrial stress-dependent pathways. Cell Death Dis. 10:1422019. View Article : Google Scholar
13	Salmela AL, Pouwels J, Varis A, Kukkonen AM, Toivonen P, Halonen PK, Perälä M, Kallioniemi O, Gorbsky GJ and Kallio MJ: Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis. 30:1032–1040. 2009. View Article : Google Scholar : PubMed/NCBI
14	Kang KA, Piao MJ, Madduma Hewage SR, Ryu YS, Oh MC, Kwon TK, Chae S and Hyun JW: Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway. Tumor Biol. 37:9615–9624. 2016. View Article : Google Scholar
15	Su CH, Kuo CL, Lu KW, Yu FS, Ma YS, Yang JL, Chu YL, Chueh FS, Liu KC and Chung JG: Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways. Environ Toxicol. 32:1725–1741. 2017. View Article : Google Scholar : PubMed/NCBI
16	Khan N, Afaq F, Syed DN and Mukhtar H: Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis. 29:1049–1056. 2008. View Article : Google Scholar : PubMed/NCBI
17	Lee WR, Shen SC, Lin HY, Hou WC, Yang LL and Chen YC: Wogonin and fisetin induce apoptosis in human promyelo-leukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endo-nuclease. Biochem Pharmacol. 63:225–236. 2002. View Article : Google Scholar : PubMed/NCBI
18	Chen YC, Shen SC, Lee WR, Lin HY, Ko CH, Shih CM and Yang LL: Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol. 76:351–359. 2002. View Article : Google Scholar : PubMed/NCBI
19	Jang KY, Jeong SJ and Kim SH, Jung JH, Kim JH, Koh W, Chen CY and Kim SH: Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Lett. 319:197–202. 2012. View Article : Google Scholar : PubMed/NCBI
20	Kim JA, Lee S, Kim DE, Kim M, Kwon BM and Han DC: Fisetin, a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter. Carcinogenesis. 36:696–706. 2015. View Article : Google Scholar : PubMed/NCBI
21	Sung B, Pandey MK and Aggarwal BB: Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol. 71:1703–1714. 2007. View Article : Google Scholar : PubMed/NCBI
22	Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H and Tian B: Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 108:84–93. 2011. View Article : Google Scholar
23	Ash D, Subramanian M, Surolia A and Shaha C: Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells. Am J Cancer Res. 5:481–497. 2015.PubMed/NCBI
24	Adan A and Baran Y: Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumor Biol. 37:5781–5795. 2016. View Article : Google Scholar
25	Adan A and Baran Y: The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks. Tumor Biol. 36:8973–8984. 2015. View Article : Google Scholar
26	Syed DN, Lall RK, Chamcheu JC, Haidar O and Mukhtar H: Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. Arch Biochem Biophys. 563:108–117. 2014. View Article : Google Scholar : PubMed/NCBI
27	Smith ML, Murphy K, Doucette CD, Greenshields AL and Hoskin DW: The dietary flavonoid fisetin causes cell cycle arrest, caspase-dependent apoptosis, and enhanced cytotoxicity of chemotherapeutic drugs in triple-negative breast cancer cells. J Cell Biochem. 117:1913–1925. 2016. View Article : Google Scholar : PubMed/NCBI
28	Murtaza I, Adhami VM, Hafeez BB, Saleem M and Mukhtar H: Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer. 125:2465–2473. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT and Hsieh YH: Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 86:263–273. 2012. View Article : Google Scholar
30	Lim DY and Park JH: Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol. 296:G1060–G1068. 2009. View Article : Google Scholar : PubMed/NCBI
31	Suh Y, Afaq F, Johnson JJ and Mukhtar H: A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 30:300–307. 2009. View Article : Google Scholar
32	Pal HC, Sharma S, Elmets CA, Athar M and Afaq F: Fisetin inhibits growth, induces G₂/M arrest and apoptosis of human epidermoid carcinoma A431 cells: Role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol. 22:470–475. 2013. View Article : Google Scholar : PubMed/NCBI
33	Zhang XJ and Jia SS: Fisetin inhibits laryngeal carcinoma through regulation of AKT/NF-κB/mTOR and ERK1/2 signaling pathways. Biomed Pharmacother. 83:1164–1174. 2016. View Article : Google Scholar : PubMed/NCBI
34	Li YS, Qin XJ and Dai W: Fisetin suppresses malignant proliferation in human oral squamous cell carcinoma through inhibition of Met/Src signaling pathways. Am J Transl Res. 9:5678–5683. 2017.
35	Shih YL, Hung FM, Lee CH, Yeh MY, Lee MH, Lu HF, Chen YL, Liu JY and Chung JG: Fisetin induces apoptosis of HSC3 human oral cancer cells through endoplasmic reticulum stress and dysfunction of mitochondria-mediated signaling pathways. In Vivo. 31:1103–1114. 2017.PubMed/NCBI
36	Sowa M, Slepokura K and Matczak-Jon E: A 1:2 cocrystal of genistein with isonicotinamide: Crystal structure and Hirshfeld surface analysis. Acta Crystallogr C. 69:1267–1272. 2013. View Article : Google Scholar : PubMed/NCBI
37	Sowa M, Slepokura K and Matczak-Jon E: Improving solubility of fisetin by cocrystallization. Cryst Eng Comm. 16:105922014. View Article : Google Scholar
38	Kadari A, Gudem S, Kulhari H, Bhandi MM, Borkar RM, Kolapalli VR and Sistla R: Enhanced oral bioavailability and anticancer efficacy of fisetin by encapsulating as inclusion complex with HPβCD in polymeric nanoparticles. Drug Deliv. 24:224–232. 2017. View Article : Google Scholar : PubMed/NCBI
39	Ragelle H, Crauste-Manciet S, Seguin J, Brossard D, Scherman D, Arnaud P and Chabot GG: Nanoemulsion formulation of fisetin improves bioavailability and antitumour activity in mice. Int J Pharm. 427:452–459. 2012. View Article : Google Scholar : PubMed/NCBI
40	Smith MA and Houghton P: A proposal regarding reporting of in vitro testing results. Clin Cancer Res. 19:2828–2833. 2013. View Article : Google Scholar : PubMed/NCBI
41	Klimaszewska-Wisniewska A, Halas-Wisniewska M, Tadrowski T, Gagat M, Grzanka D and Grzanka A: Paclitaxel and the dietary flavonoid fisetin: A synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells. Cancer Cell Int. 16:102016. View Article : Google Scholar : PubMed/NCBI
42	Klimaszewska-Wiśniewska A, Hałas-Wiśniewska M, Grzanka A and Grzanka D: Evaluation of anti-metastatic potential of the combination of fisetin with paclitaxel on A549 non-small cell lung cancer cells. Int J Mol Sci. 19:E6612018. View Article : Google Scholar
43	Tripathi R, Samadder T, Gupta S, Surolia A and Shaha C: Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. 10:255–268. 2011. View Article : Google Scholar : PubMed/NCBI
44	Khan N, Afaq F, Khusro FH, Mustafa Adhami V, Suh Y and Mukhtar H: Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 130:1695–1705. 2012. View Article : Google Scholar
45	Atashrazm F, Lowenthal RM, Dickinson JL, Holloway AF and Woods GM: Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo. Oncotarget. 19:46028–46041. 2016.
46	Moloudi K, Neshasteriz A, Hosseini A, Eyvazzadeh N, Shomali M, Eynali S, Mirzaei E and Azarnezhad A: Synergistic effects of arsenic trioxide and radiation: Triggering the intrinsic pathway of apoptosis. Iran Biomed J. 21:330–337. 2017. View Article : Google Scholar : PubMed/NCBI
47	Bandaruk Y, Mukai R and Terao J: Cellular uptake of quercetin and luteolin and their effects on monoamine oxidase-A in human neuroblastoma SH-SY5Y cells. Toxicol Rep. 1:639–649. 2014. View Article : Google Scholar : PubMed/NCBI
48	Shia CS, Tsai SY, Kuo SC, Hou YC and Chao PD: Metabolism and pharmacokinetics of 3,3′,4′,7-tetrahydroxyflavone (fisetin), 5-hydroxyflavone, and 7-hydroxyflavone and antihemolysis effects of fisetin and its serum metabolites. J Agric Food Chem. 57:83–89. 2009. View Article : Google Scholar
49	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
50	Chou TC: Theoretical basis, experimental design, and comput-erized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 58:621–681. 2006. View Article : Google Scholar : PubMed/NCBI
51	Chou TC: Preclinical versus clinical drug combination studies. Leuk Lymphoma. 49:2059–2080. 2008. View Article : Google Scholar : PubMed/NCBI
52	Gagat M, Grzanka D, Izdebska M and Grzanka A: Effect of L-homocysteine on endothelial cell-cell junctions following F-actin stabilization through tropomyosin-1 overexpression. Int J Mol Med. 32:115–129. 2013. View Article : Google Scholar : PubMed/NCBI
53	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
54	Shim MJ, Kim HJ, Yang SJ, Lee IS, Choi HI and Kim T: Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: Possible involvement of p38 MAP kinase. J Biochem Mol Biol. 35:377–383. 2011.
55	Song LL, Tu YY, Xia L, Wang WW, Wei W, Ma CM, Wen DH, Lei H, Xu HZ and Wu YL: Targeting catalase but not peroxiredoxins enhances arsenic trioxide-induced apoptosis in K562 cells. PLoS One. 9:e1049852014. View Article : Google Scholar : PubMed/NCBI
56	Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Huang Y, Tang W, Shi GY, Sun YP, Dai J, et al: Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst. 91:772–778. 1999. View Article : Google Scholar : PubMed/NCBI
57	Larson RA: Is there a best TKI for chronic phase CML? Blood. 126:2370–2375. 2015. View Article : Google Scholar : PubMed/NCBI
58	Santos FP and Ravandi F: Advances in treatment of chronic myelogenous leukemia new treatment options with tyrosine kinase inhibitors. Leuk Lymphoma. 50(Suppl 2): S16–S26. 2009. View Article : Google Scholar
59	Cui S, Wang J, Wu Q, Qian J, Yang C and Bo P: Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways. Oncotarget. 8:21674–21691. 2017.PubMed/NCBI
60	Chen HH, Chen SP, Zheng QL, Nie SP, Li WJ, Hu XJ and Xie MY: Genistein promotes proliferation of human cervical cancer cells through estrogen receptor-mediated PI3K/Akt-NF-κB pathway. J Cancer. 9:288–295. 2018. View Article : Google Scholar :
61	Guo JM, Xiao BX, Liu DH, Grant M, Zhang S, Lai YF, Guo YB and Liu Q: Biphasic effect of daidzein on cell growth of human colon cancer cells. Food Chem Toxicol. 42:1641–1646. 2004. View Article : Google Scholar : PubMed/NCBI
62	Fogarty CE and Bergmann A: Killers creating new life: Caspases drive apoptosis-induced proliferation in tissue repair and disease. Cell Death Differ. 24:1390–1400. 2017. View Article : Google Scholar : PubMed/NCBI
63	Rudrapatna VA, Bangi E and Cagan RL: Caspase signalling in the absence of apoptosis drives JNK-dependent invasion. EMBO Rep. 14:172–177. 2013. View Article : Google Scholar : PubMed/NCBI
64	Ryoo HD and Bergmann A: The role of apoptosis-induced proliferation for regeneration and cancer. Cold Spring Harb Perspect Biol. 4:a0087972012. View Article : Google Scholar : PubMed/NCBI
65	Gdynia G, Grund K, Eckert A, Böck BC, Funke B, Macher-Goeppinger S, Sieber S, Herold-Mende C, Wiestler B, Wiestler OD and Roth W: Basal caspase activity promotes migration and invasiveness in glioblastomacells. Mol Cancer Res. 5:1232–1240. 2007. View Article : Google Scholar
66	Mukai M, Kusama T, Hamanaka Y, Koga T, Endo H, Tatsuta M and Inoue M: Cross talk between apoptosis and invasion signaling in cancer cells through caspase-3 activation. Cancer Res. 65:9121–9125. 2005. View Article : Google Scholar : PubMed/NCBI
67	Portela M and Richardson HE: Death takes a holiday-non-apoptotic role for caspases in cell migration and invasion. EMBO Rep. 14:107–108. 2013. View Article : Google Scholar : PubMed/NCBI
68	Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS and Li CY: Apoptotic cells activate the 'phoenix rising' pathway to promote wound healing and tissue regeneration. Sci Signal. 3:ra132010. View Article : Google Scholar
69	Huang Q, Li F, Liu X, Li W, Shi W, Liu F, O'Sullivan B, He Z, Peng Y, Tan AC, et al: Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med. 17:860–866. 2011. View Article : Google Scholar : PubMed/NCBI
70	Donato AL, Huang Q, Liu X, Li F, Zimmerman MA and Li CY: Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy. J Invest Dermatol. 134:1686–1692. 2014. View Article : Google Scholar : PubMed/NCBI
71	Cheng J, Tian L, Ma J, Gong Y, Zhang Z, Chen Z, Xu B, Xiong H, Li C and Huang Q: Dying tumor cells stimulate proliferation of living tumor cells via caspase-dependent protein kinase Cδ activation in pancreatic ductal adenocarcinoma. Mol Oncol. 9:105–114. 2015. View Article : Google Scholar
72	Cheng J, He S, Wang M, Zhou L, Zhang Z, Feng X, Yu Y, Ma J, Dai C, Zhang S, et al: The caspase-3/PKCδ/Akt/VEGF-A signaling pathway mediates tumor repopulation during radiotherapy. Clin Cancer Res. 25:3732–3743. 2019. View Article : Google Scholar : PubMed/NCBI
73	Stevenson DE, Cooney JM, Jensen DJ, Wibisono R, Adaim A, Skinner MA and Zhang J: Comparison of enzymically gluc-uronidated flavonoids with flavonoid aglycones in an in vitro cellular model of oxidative stress protection. In Vitro Cell Dev Biol Anim. 44:73–80. 2008. View Article : Google Scholar : PubMed/NCBI
74	Zeng M, Sun R, Basu S, Ma Y, Ge S, Yin T, Gao S, Zhang J and Hu M: Disposition of flavonoids via recycling: Direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides. Mol Nutr Food Res. 60:1006–1019. 2016. View Article : Google Scholar : PubMed/NCBI
75	Sak K: In vitro cytotoxic activity of flavonoids on human ovarian cancer cell lines. Cancer Sci Res. 2:1–13. 2015. View Article : Google Scholar
76	Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D and Ran S: Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 74:5421–5434. 2014. View Article : Google Scholar : PubMed/NCBI
77	Daenen LG, Roodhart JM, van Amersfoort M, Dehnad M, Roessingh W, Ulfman LH, Derksen PW and Voest EE: Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Res. 71:6976–6985. 2011. View Article : Google Scholar : PubMed/NCBI
78	Ovcharenko A, Granot G, Rokah OH, Park J, Shpilberg O and Raanani P: Enhanced adhesion/migration and induction of Pyk2 expression in K562 cells following imatinib exposure. Leuk Res. 37:1729–1736. 2013. View Article : Google Scholar : PubMed/NCBI
79	Molli PR, Pradhan MB, Advani SH and Naik NR: RhoA: A therapeutic target for chronic myeloid leukemia. Mol Cancer. 11:162012. View Article : Google Scholar : PubMed/NCBI
80	Qi P, Tang R, Liu F and Zhou J: MicroRNA-186 regulates cell malignancy by targeting ROCK1 in chronic myeloid leukemia. Int J Clin Exp Pathol. 10:6290–6298. 2017.
81	Martini M, DeSantis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014. View Article : Google Scholar : PubMed/NCBI
82	Mirabilii S, Ricciardi MR, Piedimonte M, Gianfelici V, Bianchi MP and Tafuri A: Biological aspects of mTOR in leukemia. Int J Mol Sci. 19:E23962018. View Article : Google Scholar : PubMed/NCBI
83	Xu H, Tian Y, Yuan X, Wu H, Liu Q, Pestell RG and Wu K: The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther. 8:3783–3792. 2015.
84	Chang G, Zhang H, Wang J, Zhang Y, Xu H, Wang C, Zhang H, Ma L, Li Q and Pang T: CD44 targets Wnt/β-catenin pathway to mediate the proliferation of K562 cells. Cancer Cell Int. 13:1172013. View Article : Google Scholar
85	Chou YS and Yang MH: Epithelial-mesenchymal transition-related factors in solid tumor and hematological malignancy. J Chinese Med Assoc. 78:438–445. 2015. View Article : Google Scholar
86	Chen SC, Liao TT and Yang MH: Emerging roles of epithelial-mesenchymal transition in hematological malignancies. J Biomed Sci. 25:372018. View Article : Google Scholar : PubMed/NCBI
87	Kahlert UD, Joseph JV and Kruyt FAE: EMT- and MET-related processes in nonepithelial tumors: Importance for disease progression, prognosis, and therapeutic opportunities. Mol Oncol. 11:860–877. 2017. View Article : Google Scholar : PubMed/NCBI
88	Wang N, Guo D, Zhao YY, Dong CY, Liu XY, Yang BX, Wang SW, Wang L, Liu QG, Ren Q, et al: TWIST-1 promotes cell growth, drug resistance and progenitor clonogenic capacities in myeloid leukemia and is a novel poor prognostic factor in acute myeloid leukemia. Oncotarget. 6:20977–20992. 2015.PubMed/NCBI
89	Cosset E, Hamdan G, Jeanpierre S, Voeltzel T, Sagorny K, Hayette S, Mahon FX, Dumontet C, Puisieux A, Nicolini FE and Maguer-Satta V: Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia. Blood. 117:1673–1676. 2011. View Article : Google Scholar
90	Kidan N, Khamaisie H, Ruimi N, Roitman S, Eshel E, Dally N, Ruthardt M and Mahajna J: Ectopic expression of Snail and Twist in Ph+ Leukemia cells upregulates CD44 expression and alters their differentiation potential. J Cancer. 8:3952–3968. 2017. View Article : Google Scholar : PubMed/NCBI
91	Touil YS, Seguin J, Scherman D and Chabot GG: Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice. Cancer Chemother Pharmacol. 68:445–455. 2011. View Article : Google Scholar
92	O'Dwyer ME, La Rosée P, Nimmanapalli R, Bhalla KN and Druker BJ: Recent advances in Philadelphia chromosome-positive malignancies: The potential role of arsenic trioxide. Semin Hematol. 39(2 Suppl): S18–S21. 2002. View Article : Google Scholar
93	O'Dwyer M: Multifaceted approach to the treatment of bcrabl-positive leukemias. Oncologist. 7(Suppl 1): S30–S38. 2002. View Article : Google Scholar
94	Potin S, Bertoglio J and Bréard J: Involvement of a Rho-ROCK-JNK pathway in arsenic trioxide-induced apoptosis in chronic myelogenous leukemia cells. FEBS Lett. 581:118–124. 2007. View Article : Google Scholar
95	Yan H, Wang YC, Li D, Wang Y, Liu W, Wu YL and Chen GQ: Arsenic trioxide and proteasome inhibitor bortezomib synergis-tically induce apoptosis in leukemic cells: The role of protein kinase Cdelta. Leukemia. 27:1488–1495. 2007. View Article : Google Scholar
96	El Eit RM, Iskandarani AN, Saliba JL, Jabbour MN, Mahfouz RA, Bitar NM, Ayoubi HR, Zaatari GS, Mahon FX, De Thé HB, et al: Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha. Int J Cancer. 134:988–996. 2014. View Article : Google Scholar
97	Xu W, Wei W, Yu Q, Wu C, Ye C, Wu Y and Yan H: Arsenic trioxide and bortezomib interact synergistically to induce apoptosis in chronic myelogenous leukemia cells resistant to imatinibmesylate through Bcr/Abl-dependent mechanisms. Mol Med Rep. 10:1519–1524. 2014. View Article : Google Scholar : PubMed/NCBI
98	La Rosée P, Johnson K, O'Dwyer ME and Druker BJ: In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol. 30:729–737. 2002. View Article : Google Scholar : PubMed/NCBI