Induction of cell cycle arrest via the p21, p27–cyclin E,A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol

Open access

Abstract

Clioquinol has been shown to have anticancer activity in several carcinoma cells. In this study, we preliminarily examined the effect of clioquinol in human SMMC-7721 hepatoma and QSG-7701 normal hepatic cells. Our results indicated that clioquinol did not significantly affect survival of QSG-7701 cells, whereas it reduced cell viability in a concentration- and time-dependent manner in SMMC-7721 cells. Clioquinol did not trigger autophagy and apoptosis, while it induced cell cycle arrest in the S-phase in SMMC- 7721 cells. Additionally, down-regulation of cyclin D1, A2, E1, Cdk2 and up-regulation of p21, p27 were detected after the treatment with clioquinol. The results demonstrated for the first time that clioquinol suppressed cell cycle progression in the S-phase in SMMC-7721 cells via the p21, p27-cyclin E,A/Cdk2 pathway. This suggests that clioquinol may have a therapeutic potential as an anticancer drug for certain malignances.

References

  • 1. L. Cahoon, The curious case of clioquinol, Nat. Med. 15 (2009) 356-359; DOI: 10.1038/nm0409-356.

  • 2. J. Tateishi, Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals, Neuropathology 20 (2000) S20-S24; DOI: 10.1046/j.1440-1789.2000.00296.x.

  • 3. T. Tsubaki, Y. Honma and M. Hoshi, Neurological syndrome associated with clioquinol, Lancet 1 (1971) 696-697.

  • 4. L. Helmuth, Neuroscience. An antibiotic to treat Alzheimer’s? Science 290 (2000) 1273-1274; DOI: 10.1126/science.290.5495.1273a.

  • 5. X. Mao and A. D. Schimmer, The toxicology of clioquinol, Toxicol. Lett. 182 (2008) 1-6; DOI: 10.1016/j.toxlet.2008.08.015.

  • 6. M. H. Park, S. J. Lee, H. R. Byun, Y. Kim, Y. J. Oh, J. Y. Koh and J. J. Hwang, Clioquinol induces autophagy in cultured astrocytes and neurons by acting as a zinc ionophore, Neurobiol. Dis. 42 (2011) 242-251; DOI: 10.1016/j.nbd.2011.01.009.

  • 7. S. R. Bareggi and U. Cornelli, Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders, CNS Neurosci. Ther. 18 (2012) 41-46; DOI: 10.1111/j.1755-5949.2010. 00231.x.

  • 8. K. G. Daniel, D. Chen, S. Orlu, Q. C. Cui, F. R. Miller and Q. P. Dou, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteosome inhibitors and apoptosis inducers in human breast cancer cells, Breast Cancer Res. 7 (2005) 897-908; DOI: 10.1186/bcr1322.

  • 9. T. Du, G. Filiz, A. Caragounis, P. J. Crouch and A. R. White, Clioquinol promotes cancer cell toxicity through tumor necrosis factor alpha release from macrophages, J. Pharmacol. Exp. Ther. 324 (2008) 360-367; DOI: 10.1124/jpet.107.130377.

  • 10. M. W. Lee, P. C. Lin and W. C. Tsai, The anti-cancer effects of clioquinol on oral cancer, EACR-23 Poster Sessions/Eur. J. Cancer 50 (2014) S42.

  • 11. O. Afzal, S. Kumar, M. R. Haider, M. R. Ali, R. Kumar, M. Jaggi and S. Baw, A review on anticancer potential of bioactive heterocycle quinolone, Eur. J. Med. Chem. 97 (2015) 871-910; DOI: 10.1016/j. ejmech.2014.07.044.

  • 12. W . Q. Ding, B. Liu, J. L. Vaught, H. Yamauchi and S. E. Lind, Anti-cancer activity of the antibiotic clioquinol, Cancer Res. 65 (2005) 3389-3395; DOI: 10.1158/0008-5472.CAN-04 -3577.

  • 13. X. Mao, X. Li, R. Sprangers, X. Wang, A. Venugopal, T. Wood, Y. Zhang, D. A. Kuntz, E. Coe, S. Trudel, D. Rose, R. A. Batey, L. E. Kay and A. D. Schimmer, Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma, Leukemia 23 (2009) 585-590; DOI: 10.1038/leu.2008.232.

  • 14. A. D. Schimmer, Y. Jitkova, M. Gronda, Z. Wang, J. Brandwein, C. Chen, V. Gupta, A. Schuh, K. Yee, J. Chen, S. Ackloo, T. Booth, S. Keays and M. D. Minden, A Phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies, Clin. Lymphoma Myeloma Leuk. 12 (2012) 330-336; DOI: 10.1016/j.clml.2012.05.005.

  • 15. T. Kanzawa, Y. Kondo, H. Ito, S. Kondo and I. Germano, Induction of autophagic cell death in malignant glioma cells by arsenic trioxide, Cancer Res. 63 (2003) 2103-2108.

  • 16. K. J. Livak and T. D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2-delta delta CT method, Methods 52 (2001) 402-408; DOI: 10.1006/ meth.2001.1262.

  • 17. H. Yu, Y. Zhou, S. E. Lind and W. Q. Ding, Clioquinol targets zinc to lysosomes in human cancer cells, Biochem. J. 417 (2009) 133-139; DOI: 10.1042/BJ20081421.

  • 18. H. Yu, J. R. Lou and W. Q. Ding, Clioquinol independently targets NF kappa B and lysosome pathways in human cancer cells, Anticancer Res. 30 (2010) 2087-2092.

  • 19. D. Chen, Q. C. Cui, H. Yang, R. A. Barrea, F. H. Sarkar, S. Sheng, B. Yan, G. P. Reddy and Q. P. Dou, Clioquinol, a therapeutic agent for Alzheimer’s disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts, Cancer Res. 67 (2007) 1636-1644; DOI: 10.1158/0008-5472. CAN -06-3546.

  • 20. M. A. Cater and Y. Haupt, Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer, Biochem. J. 436 (2011) 481-491; DOI: 10.1042/BJ20110123.

  • 21. M. Katsuyama, K. Iwata, M. Ibi, K. Matsunob, M. Matsumotob and C. Yabe-Nishimura, Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling, Toxicology 299 (2012) 55-59; DOI: 10.1016/j.tox.2012.05.013.

  • 22. C. Laezza, S. Pisanti, E. Crescenzi and M. Bifulco, Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells, FEBS Lett. 580 (2006) 6076-6082; DOI:10.1016/j.febslet.2006.09.074.

  • 23. E. J. Yeo, J. H. Ryu, Y. S. Chun, Y. S. Cho, I. J. Jang, H. Cho, J. Kim, M. S. Kim and J. W. Park, YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases, Cancer Res. 66 (2006) 6345-6352; DOI: 10.1158/0008-5472.CAN-05-4460.

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

Journal Information


IMPACT FACTOR 2016: 1.288
5-year IMPACT FACTOR: 1.600

CiteScore 2016: 1.55

SCImago Journal Rank (SJR) 2016: 0.353
Source Normalized Impact per Paper (SNIP) 2016: 0.854

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 31 31 23
PDF Downloads 8 8 7