* Corresponding Author
Mechanism of cytotoxic activity of chalcone derivatives against K562 leukemia cell lines
https://doi.org/10.19106/JMedSci004904201701 Arina Novilla(1*), . Mustofa(2), Indwiani Astuti(3), . Jumina(4), Hery Suwito(5)
(1) Doctoral Program of Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Department of Medical Laboratory Technology, School of Health Sciences Jenderal Achmad Yani, Cimahi
(2) Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta
(3) Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta
(5) Department of Biology, Faculty of Science and Technology, Airlangga University, Surabaya, Indonesia
(*) Corresponding Author
Abstract
Two chalcone derivatives i.e. (E)-1-(4-aminophenyl)-3-(2,3dimethoxyphenyl)-prop-2-en-1-
one (Compound-1), and (E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one) (Compound-2),
has been proven to have potential cytotoxic activity. The aim of this study was to
evaluate the effect of these compounds on PI3K/Akt signalling pathway in K562 cell
lines. After incubation with the tested compounds, AKT, caspase-3, STAT3 and cyclin
D1 concentrations were measured using ELISA. Furthermore, cell cycle was analysed
using flowcytometry. Imatinib and isotretinoin were used as positive control, whereas
cell culture without treatment was used as negative control. The AKT concentration after
treatment with Compound-1 and -2 was significantly lower than that control, imatinib
and isotretinoin (p<0.05). The apoptotic indices after treatment with Compound-1 and
-2 were significantly higher than control, however they were lower than imatinib and
isotretinoin (p<0.05). The caspase-3 concentration after treatment with Compound-1 at
5 and 10 μg/mL and Compound-2 at 10 μg/mL was significantly higher than that control
and imatinib, however it was lower than isotretinoin (p<0.05). The STAT3 concentration
after treatment with Compound-1 and -2 was significantly lower than that control and
isotretinoin at 50 μg/mL (p<0.05) and similar with imatinib (p>0.05). The cyclin D1
concentration after treatment with Compound-1 and -2 was significantly lower than that
control, imatinib and isotretinoin (p<0.05). In addition, Compound-1 and -2 arrested G0/
G1 and G2/M phase in K562 cell lines, with comparable results to imatinib and isotretinoin.
In conclusion, the mechanism of cytotoxic activity of Compound-1 and -2 are through the
PI3K/Akt signalling pathway inhibition, apoptosis induction by upregulation of apoptotic
markers, and inhibition of cell cycle progression by regulating cell cycle-related factors.
Keywords
Full Text:
PDFReferences
Bali A, O′Brien PM, Edwards LS, Sutherland RL, Hacker NF, et al. (2004) Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clinical cancer research 10: 5168–5177. 2. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, et al. (1999) Stat3 as an oncogene. Cell 98: 295–303. 3. C Chiarini F, Lonetti A, Teti G, Orsini E, Bressanin D, Cappellini A, Ricci F, Tazzari PL, Ognibene A, Falconi M, Pagliaro P, Iacobucci I, Martinelli G, Amadori S, McCubrey JA, Martelli AM. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget. 2012;3:1615–28. 4. Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, et al. (2004) Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. Journal of Clinical Investigation 114: 720–728. 5. De Souza CP, Ellem KA, Gabrielli BG. Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp Cell Res 2000;257:11–21. 6. Di Gennaro E, Barbarino M, Bruzzese F et al. Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells. J Cell Physiol 2003;195:139–50. 7. Green DR. Apoptotic pathways: the roads to ruin. Cell 1998; 94: 695–8. 8. H.C. Dan, M. Sun, S. Kaneko, R.I. Feldman, S.V. Nicosia, H.G. Wang, B.K. Tsang, J.Q. Cheng, Akt phosphorylation and stabilization of Xlinked inhibitor of apoptosis protein (XIAP), J. Biol. Chem. 279 (2004) 5405–5412. 9. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim Biophys Acta 2004; 1697: 3–16. 10. J.H. Feng, R. Tamaskovic, Z.Z. Yang, D.P. Brazil, A. Merlo, D. Hess, B.A. Hemmings, Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation, J. Biol. Chem. 279 (2004) 35510–35517. 11. Kusume T, Tsuda H, Kawabata M, Inoue T, Umesaki N, et al. (1999) The p16-cyclin D1/CDK4-pRb pathway and clinical outcome in epithelial ovarian cancer. Clinical cancer research 5: 4152–4157. 12. L. del Peso, M. Gonzalez-Garcia, C. Page, R. Herrera, G. Nunez, Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt, Science 278 (1997) 687–689. 13. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010;1:89–103. 14. Paulovich, A.G. et al. (1997) When checkpoints fail. Cell 88, 315–321 15. Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood. 2012;119:911–923. 16. Qi, Z., Liu, M., Liu, Y., Zhang, M. and Yang, G., 2014. Tetramethoxychalcone, a chalcone derivative, suppresses proliferation, blocks cell cycle progression, and induces apoptosis of human ovarian cancer cells. PloS one, 9(9), p.e106206. 17. S.R. Datta, H. Dudek, X. Tao, S. Masters, H.A. Fu, Y. Gotoh, M.E. Greenberg, Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery, Cell 91 (1997) 231–241. 18. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004;73:39–85. 19. Shen, K.H., Chang, J.K., Hsu, Y.L. and Kuo, P.L., 2007. Chalcone arrests cell cycle progression and induces apoptosis through induction of mitochondrial pathway and inhibition of nuclear factor kappa B signalling in human bladder cancer cells. Basic & clinical pharmacology & toxicology,101(4), pp.254-261. 20. Wolter F, Akoglu B, Clausnitzer A, Stein J (2001) Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell cycle arrest in colon cancer cell lines. Journal of nutrition 131: 2197–2203. 21. Xu, S., Chen, M., Chen, W., Hui, J., Ji, J., Hu, S., Zhou, J., Wang, Y. and Liang, G., 2015. Chemopreventive effect of chalcone derivative, L2H17, in colon cancer development. BMC cancer, 15(1), p.870. 22. Y. Ogawara, S. Kishishita, T. Obata, Y. Isazawa, T. Suzuki, K. Tanaka, N. Masuyama, Y. Gotoh, Akt enhances Mdm2-mediated ubiquitination and degradation of p53, J. Biol. Chem. 277 (2002) 21843–21850. 23. Yu C, Krystal G, Varticovksi L, et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res 2002; 62: 188–99. 24. Yu H, Kortylewski M, Pardoll D (2007). Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Reviews Immunology 7: 41–51. doi: 10.1038/nri195
DOI: https://doi.org/10.19106/JMedSci004904201701
Article Metrics
Abstract views : 1997
| 
views : 2059
Copyright (c) 2017 Arina Novilla, . Mustofa, Indwiani Astuti, . Jumina, Hery Suwito
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Journal of the Medical Sciences (Berkala Ilmu Kedokteran) by Universitas Gadjah Mada is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Based on a work at http://jurnal.ugm.ac.id/bik/.