Liposome‑delivered baicalein induction of myeloid leukemia K562 cell death via reactive oxygen species generation

Wang,Scarlet  Xiaoyan; Wen,Xuesong; Bell,Celia; Appiah,Sandra

doi:10.3892/mmr.2018.8396

Liposome‑delivered baicalein induction of myeloid leukemia K562 cell death via reactive oxygen species generation

Authors:
- Scarlet Xiaoyan Wang
- Xuesong Wen
- Celia Bell
- Sandra Appiah
View Affiliations

Affiliations: Department of Natural Sciences, Faculty of Science and Technology, Middlesex University, London NW4 4BT, UK
Published online on: January 8, 2018 https://doi.org/10.3892/mmr.2018.8396
Pages: 4524-4530
Copyright: © Wang 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

Baicalein (BL), a potential cancer chemopreventative flavone, has been reported to inhibit cancer cell growth by inducing apoptosis and causing cell cycle arrest in various human cancer cell models. Delivery of BL via nanoliposomes has been shown to improve its oral bioavailability and long‑circulating property in vivo. However, the role of BL in the inhibition of human chronic myeloid leukemia (CML) K562 cell growth and its underlying mechanisms has yet to be elucidated. In the present study, BL was formulated into liposomes with different sizes to improve its solubility and stability. The cytotoxic and pro‑apoptotic effects of free BL and liposomal BL were also evaluated. The results demonstrated that 100 nm liposomes were the most stable formulation when compared with 200 and 400 nm liposomes. Liposomal BL inhibited K562 cell growth as efficiently as free BL (prepared in DMSO), indicating that the liposome may be a potential vehicle to deliver BL for the treatment of CML. Flow cytometry analysis showed that there was significant (P<0.005) cell cycle arrest in the sub‑G1 phase (compared with vehicle control), indicating cell apoptosis following 20 µM liposomal BL or free BL treatment of K562 cells for 48 h. The induction of cell apoptosis by all BL preparations was further confirmed through the staining of treated cells with Annexin V‑fluorescein isothiocyanate/propidium iodide. A significant increase in reactive oxygen species (ROS) generation was observed in free BL and liposomal BL treated cells, with a higher level of ROS produced from those treated with free BL. This indicated that cell apoptosis induced by BL may be via ROS generation and liposome delivery may further extend the effect through its long‑circulating property.

View Figures

View References

1	Wang Y, Wei S, Wang J, Fang Q and Chai Q: Phenethyl isothiocyanate inhibits growth of human chronic myeloid leukemia K562 cells via reactive oxygen species generation and caspases. Mol Med Rep. 10:543–549. 2014. View Article : Google Scholar : PubMed/NCBI
2	Melo JV and Barnes DJ: Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 7:441–453. 2007. View Article : Google Scholar : PubMed/NCBI
3	Owen HC, Appiah S, Hasan N, Ghali L, Elayat G and Bell C: Phytochemical modulation of apoptosis and autophagy: Strategies to overcome chemoresistance in leukemic stem cells in the bone marrow microenvironment. Int Rev Neurobiol. 135:249–278. 2017. View Article : Google Scholar : PubMed/NCBI
4	Yan H, Xin S, Wang H, Ma J, Zhang H and Wei H: Baicalein inhibits MMP-2 expression in human ovarian cancer cells by suppressing the p38 MAPK-dependent NF-κB signaling pathway. Anticancer Drugs. 26:649–656. 2015.PubMed/NCBI
5	Guo Z, Hu X, Xing Z, Xing R, Lv R, Cheng X, Su J, Zhou Z, Xu Z, Nilsson S and Liu Z: Baicalein inhibits prostate cancer cell growth and metastasis via the caveolin-1/AKT/mTOR pathway. Mol Cell Biochem. 406:111–119. 2015. View Article : Google Scholar : PubMed/NCBI
6	Wang N, Ren D, Deng S and Yang X: Differential effects of baicalein and its sulfated derivatives in inhibiting proliferation of human breast cancer MCF-7 cells. Chem Biol Interact. 221:99–108. 2014. View Article : Google Scholar : PubMed/NCBI
7	Peng Y, Guo C, Yang Y, Li F, Zhang Y, Jiang B and Li Q: Baicalein induces apoptosis of human cervical cancer HeLa cells in vitro. Mol Med Rep. 11:2129–2134. 2015. View Article : Google Scholar : PubMed/NCBI
8	Lee HZ, Leung HW, Lai MY and Wu CH: Baicalein induced cell cycle arrest and apoptosis in human lung squamous carcinoma CH27 cells. Anticancer Res. 25:959–964. 2005.PubMed/NCBI
9	He X, Pei L, Tong HH and Zheng Y: Comparison of spray freeze drying and the solvent evaporation method for preparing solid dispersions of baicalein with Pluronic F68 to improve dissolution and oral bioavailability. AAPS PharmSciTech. 12:104–113. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lai MY, Hsiu SL, Tsai SY, Hou YC and Chao PD: Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats. J Pharm Pharmacol. 55:205–209. 2003. View Article : Google Scholar : PubMed/NCBI
11	Liang J, Wu W, Liu Q and Chen S: Long-circulating nanoliposomes (LCNs) sustained delivery of baicalein (BAI) with desired oral bioavailability in vivo. Drug Deliv. 20:319–323. 2013. View Article : Google Scholar : PubMed/NCBI
12	de Oliveira MR, Nabavi SF, Habtemariam S, Erdogan Orhan I, Daglia M and Nabavi SM: The effects of baicalein and baicalin on mitochondrial function and dynamics: A review. Pharmacol Res. 100:296–308. 2015. View Article : Google Scholar : PubMed/NCBI
13	Zhang L, Lin G, Chang Q and Zuo Z: Role of intestinal first-pass metabolism of baicalein in its absorption process. Pharm Res. 22:1050–1058. 2005. View Article : Google Scholar : PubMed/NCBI
14	Fong YK, Li CR, Wo SK, Wang S, Zhou L, Zhang L, Lin G and Zuo Z: In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein. J Ethnopharmacol. 141:742–753. 2012. View Article : Google Scholar : PubMed/NCBI
15	Seo MJ, Choi HS, Jeon HJ, Woo MS and Lee BY: Baicalein inhibits lipid accumulation by regulating early adipogenesis and m-TOR signaling. Food Chem Toxicol. 67:57–64. 2014. View Article : Google Scholar : PubMed/NCBI
16	Tsai TH, Liu SC, Tsai PL, Ho LK, Shum AY and Chen CF: The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: A microdialysis study. Br J Pharmacol. 137:1314–1320. 2002. View Article : Google Scholar : PubMed/NCBI
17	Tian S, He G, Song J, Wang S, Xin W, Zhang D and Du G: Pharmacokinetic study of baicalein after oral administration in monkeys. Fitoterapia. 83:532–540. 2012. View Article : Google Scholar : PubMed/NCBI
18	Tan ML, Choong PF and Dass CR: Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery. Peptides. 31:184–193. 2010. View Article : Google Scholar : PubMed/NCBI
19	Huang YB, Tsai MJ, Wu PC, Tsai YH, Wu YH and Fang JY: Elastic liposomes as carriers for oral delivery and the brain distribution of (+)-catechin. J Drug Target. 19:709–718. 2011. View Article : Google Scholar : PubMed/NCBI
20	Park SJ, Choi SG, Davaa E and Park JS: Encapsulation enhancement and stabilization of insulin in cationic liposomes. Int J Pharm. 415:267–272. 2011. View Article : Google Scholar : PubMed/NCBI
21	Song YK, Hyun SY, Kim HT, Kim CK and Oh JM: Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: Comparison with ethosomes. J Microencapsul. 28:151–208. 2011. View Article : Google Scholar : PubMed/NCBI
22	Cansell M, Nacka F and Combe N: Marine lipid-based liposomes increase in vivo FA bioavailability. Lipids. 38:551–559. 2003. View Article : Google Scholar : PubMed/NCBI
23	Guan P, Lu Y, Qi J, Niu M, Lian R, Hu F and Wu W: Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt. Int J Nanomedicine. 6:965–974. 2011.PubMed/NCBI
24	Isacchi B, Arrigucci S, La Marca G, Bergonzi MC, Vannucchi MG, Novelli A and Bilia AR: Conventional and long-circulating liposomes of artemisinin: Preparation, characterization, and pharmacokinetic profile in mice. J Liposome Res. 21:237–244. 2011. View Article : Google Scholar : PubMed/NCBI
25	Vural I, Sarisozen C and Olmez SS: Chitosan coated furosemide liposomes for improved bioavailability. J Biomed Nanotechnol. 7:426–430. 2011. View Article : Google Scholar : PubMed/NCBI
26	Kim HP, Son KH, Chang HW and Kang SS: Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci. 96:229–245. 2004. View Article : Google Scholar : PubMed/NCBI
27	Lu Y, Joerger R and Wu C: Study of the chemical composition and antimicrobial activities of ethanolic extracts from roots of Scutellaria baicalensis Georgi. J Agric Food Chem. 59:10934–10942. 2011. View Article : Google Scholar : PubMed/NCBI
28	Shieh DE, Liu LT and Lin CC: Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin. Anticancer Res. 20:2861–2865. 2000.PubMed/NCBI
29	Chao JI, Su WC and Liu HF: Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. Mol Cancer Ther. 6:3039–3048. 2007. View Article : Google Scholar : PubMed/NCBI
30	Chen H, Gao Y, Wu J, Chen Y, Chen B, Hu J and Zhou J: Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies. Cancer Lett. 354:5–11. 2014. View Article : Google Scholar : PubMed/NCBI
31	Cheng YH, Li LA, Lin P, Cheng LC, Hung CH, Chang NW and Lin C: Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation. Toxicol Appl Pharmacol. 263:360–367. 2012. View Article : Google Scholar : PubMed/NCBI
32	Ma GZ, Liu CH, Wei B, Qiao J, Lu T, Wei HC, Chen HD and He CD: Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation. Inflammation. 36:457–467. 2013. View Article : Google Scholar : PubMed/NCBI
33	Chow JM, Shen SC, Wu CY and Chen YC: 12-o-Tetradecanoylphorbol 13-acetate prevents baicalein-induced apoptosis via activation of protein kinase C and JNKs in human leukemia cells. Apoptosis. 11:1999–2011. 2006. View Article : Google Scholar : PubMed/NCBI
34	Lee JH, Li YC, Ip SW, Hsu SC, Chang NW, Tang NY, Yu CS, Chou ST, Lin SS, Lino CC, et al: The role of Ca²⁺ in baicalein-induced apoptosis in human breast MDA-MB-231 cancer cells through mitochondria- and caspase-3-dependent pathway. Anticancer Res. 28:1701–1711. PubMed/NCBI
35	Wang X, Li D, Ghali L, Xia R, Munoz LP, Garelick H, Bell C and Wen X: Therapeutic potential of delivering arsenic trioxide into HPV infected cervical cancer cells using liposomal nanotechnology. Nanoscale Res Lett. 11:942016. View Article : Google Scholar : PubMed/NCBI
36	Wang SX, Michiels J, Ariën KK, New R, Vanham G and Roitt I: Inhibition of HIV virus by neutralizing Vhh attached to dual functional liposomes encapsulating dapivirine. Nanoscale Res Lett. 11:3502016. View Article : Google Scholar : PubMed/NCBI
37	Berger N, Sachse A, Bender J, Schubert R and Brandl M: Filter extrusion of liposomes using different devices: Comparison of liposome size, encapsulation efficiency and process characteristics. Int J Pharm. 223:55–68. 2001. View Article : Google Scholar : PubMed/NCBI
38	Clayton R, Ohagen A, Nicol F, Del Vecchio AM, Jonckers TH, Goethals O, Van Loock M, Michiels L, Grigsby J, Xu Z, et al: Sustained and specific in vitro inhibition of HIV-1 replication by a protease inhibitor encapsulated in gp120-targeted liposomes. Antiviral Res. 84:142–149. 2009. View Article : Google Scholar : PubMed/NCBI
39	Lee JS, Hwang SY and Lee EK: Imaging-based analysis of liposome internalization to macrophage cells: Effects of liposome size and surface modification with PEG moiety. Colloids Surf B Biointerfaces. 136:786–790. 2015. View Article : Google Scholar : PubMed/NCBI
40	Feng J, Iyer A, Seo Y, Broaddus C, Liu B, VanBrocklin H and He J: Effects of size and targeting ligand on biodistribution of liposome nanoparticles in tumor mice. Soc Nucl Med Annu Meet Abstr. 54:13392013.
41	Ye F, Wang H, Zhang L, Zou Y, Han H and Huang J: Baicalein induces human osteosarcoma cell line MG-63 apoptosis via ROS-induced BNIP3 expression. Tumor Biol. 36:4731–4740. 2015. View Article : Google Scholar
42	Reczek CR and Chandel NS: The two faces of reactive oxygen species in cancer. Annu Rev Cancer Biol. 1:79–98. 2017. View Article : Google Scholar
43	Galadari S, Rahman A, Pallichankandy S and Thayyullathil F: Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic Biol Med. 104:144–164. 2017. View Article : Google Scholar : PubMed/NCBI
44	Liou GY and Storz P: Reactive oxygen species in cancer. Free Radic Res. 44:479–496. 2010. View Article : Google Scholar : PubMed/NCBI
45	Nieborowska-Skorska M, Kopinski PK, Ray R, Hoser G, Ngaba D, Flis S, Cramer K, Reddy MM, Koptyra M, Penserga T, et al: Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors. Blood. 119:4253–4263. 2012. View Article : Google Scholar : PubMed/NCBI
46	Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar : PubMed/NCBI
47	Cadenas E: Mitochondrial free radical production and cell signaling. Mol Aspects Med. 25:17–26. 2004. View Article : Google Scholar : PubMed/NCBI
48	Wang J, Yu Y, Hashimoto F, Sakata Y, Fujii M and Hou DX: Baicalein induces apoptosis through ROS-mediated mitochondrial dysfunction pathway in HL-60 cells. Int J Mol Med. 14:627–632. 2004.PubMed/NCBI
49	Choi EO, Park C, Hwang HJ, Hong SH, Kim GY, Cho EJ, Kim WJ and Choi YH: Baicalein induces apoptosis via ROS-dependent activation of caspases in human bladder cancer 5637 cells. Int J Oncol. 49:1009–1018. 2016. View Article : Google Scholar : PubMed/NCBI