Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Novel SIRT Inhibitor, MHY2256, Induces Cell Cycle Arrest, Apoptosis, and Autophagic Cell Death in HCT116 Human Colorectal Cancer Cells

  • Kim, Min Jeong (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kang, Young Jung (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Sung, Bokyung (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Jang, Jung Yoon (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Ahn, Yu Ra (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Oh, Hye Jin (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Choi, Heejeong (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Choi, Inkyu (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Im, Eunok (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Moon, Hyung Ryong (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Chung, Hae Young (Division of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Nam Deuk (Division of Pharmacy, College of Pharmacy, Pusan National University)
  • Received : 2020.09.02
  • Accepted : 2020.09.25
  • Published : 2020.11.01
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Abstract

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

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References

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. and Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394-424. https://doi.org/10.3322/caac.21492
  2. Bultman, S. J. (2017) Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol. Nutr. Food Res. 61, 1500902.
  3. Choi, P. R., Kang, Y. J., Sung, B., Kim, J. H., Moon, H. R., Chung, H. Y., Kim, S. E., Park, M. I., Park, S. J. and Kim, N. D. (2015) MHY218-induced apoptotic cell death is enhanced by the inhibition of autophagy in AGS human gastric cancer cells. Int. J. Oncol. 47, 563-572. https://doi.org/10.3892/ijo.2015.3031
  4. Dai, H., Sinclair, D. A., Ellis, J. L. and Steegborn, C. (2018) Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol. Ther. 188, 140-154. https://doi.org/10.1016/j.pharmthera.2018.03.004
  5. De, U., Son, J. Y., Sachan, R., Park, Y. J., Kang, D., Yoon, K., Lee, B. M., Kim, I. S., Moon, H. R. and Kim, H. S. (2018) A new synthetic histone deacetylase inhibitor, MHY2256, induces apoptosis and autophagy cell death in endometrial cancer cells via p53 acetylation. Int. J. Mol. Sci. 19, 2743. https://doi.org/10.3390/ijms19092743
  6. Heltweg, B., Gatbonton, T., Schuler, A. D., Posakony, J., Li, H., Goehle, S., Kollipara, R., Depinho, R. A., Gu, Y., Simon, J. A. and Bedalov, A. (2006) Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368-4377. https://doi.org/10.1158/0008-5472.CAN-05-3617
  7. Heo, G., Kang, D., Park, C., Kim, S. J., Choo, J., Lee, Y., Yoo, J. W., Jung, Y., Lee, J., Kim, N. D., Chung, H. Y., Moon, H. R. and Im, E. (2019) Pro-apoptotic effect of the novel benzylidene derivative MHY695 in human colon cancer cells. Oncol. Lett. 18, 3256-3264.
  8. Hu, J., Jing, H. and Lin, H. (2014) Sirtuin inhibitors as anticancer agents. Future Med. Chem. 6, 945-966. https://doi.org/10.4155/fmc.14.44
  9. Hwangbo, H., Kim, S. Y., Lee, H., Park, S. H., Hong, S. H., Park, C., Kim, G. Y., Leem, S. H., Hyun, J. W., Cheong, J. and Choi, Y. H. (2020) Auranofin enhances sulforaphane-mediated apoptosis in hepatocellular carcinoma Hep3B cells through inactivation of the PI3K/Akt signaling pathway. Biomol. Ther. (Seoul) 28, 443-455. https://doi.org/10.4062/biomolther.2020.122
  10. Jang, J. Y., Kang, Y. J., Sung, B., Kim, M. J., Park, C., Kang, D., Moon, H. R., Chung, H. Y. and Kim, N. D. (2018) MHY440, a novel topoisomerase Ι inhibitor, induces cell cycle arrest and apoptosis via a ROS-dependent DNA damage signaling pathway in AGS human gastric cancer cells. Molecules 24, 96. https://doi.org/10.3390/molecules24010096
  11. Jiang, Y., Liu, J., Chen, D., Yan, L. and Zheng, W. (2017) Sirtuin inhibition: strategies, inhibitors, and therapeutic potential. Trends Pharmacol. Sci. 38, 459-472. https://doi.org/10.1016/j.tips.2017.01.009
  12. Kaufmann, S. H., Lee, S. H., Meng, X. W., Loegering, D. A., Kottke, T. J., Henzing, A. J., Ruchaud, S., Samejima, K. and Earnshaw, W. C. (2008) Apoptosis-associated caspase activation assays. Methods 44, 262-272. https://doi.org/10.1016/j.ymeth.2007.11.005
  13. Lain, S., Hollick, J. J., Campbell, J., Staples, O. D., Higgins, M., Aoubala, M., McCarthy, A., Appleyard, V., Murray, K. E., Baker, L., Thompson, A., Mathers, J., Holland, S. J., Stark, M. J., Pass, G., Woods, J., Lane, D. P. and Westwood, N. J. (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454-463. https://doi.org/10.1016/j.ccr.2008.03.004
  14. Lee, Y., Sung, B., Kang, Y. J., Kim, D. H., Jang, J. Y., Hwang, S. Y., Kim, M., Lim, H. S., Yoon, J. H., Chung, H. Y. and Kim, N. D. (2014) Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Int. J. Oncol. 44, 1599-1606. https://doi.org/10.3892/ijo.2014.2339
  15. Liu, S. L., Liu, Z., Zhang, L. D., Zhu, H. Q., Guo, J. H., Zhao, M., Wu, Y. L., Liu, F. and Gao, F. H. (2017) $GSK3{\beta}$-dependent cyclin D1 and cyclin E1 degradation is indispensable for NVP-BEZ235 induced G0/G1 arrest in neuroblastoma cells. Cell Cycle 16, 2386-2395. https://doi.org/10.1080/15384101.2017.1383577
  16. Martinez-Redondo, P. and Vaquero, A. (2013) The diversity of histone versus nonhistone sirtuin substrates. Genes Cancer 4, 148-163. https://doi.org/10.1177/1947601913483767
  17. Mellini, P., Carafa, V., Di Rienzo, B., Rotili, D., De Vita, D., Cirilli, R., Gallinella, B., Provvisiero, D. P., Di Maro, S., Novellino, E., Altucci, L. and Mai, A. (2012) Carprofen analogues as sirtuin inhibitors: enzyme and cellular studies. ChemMedChem 7, 1905-1908. https://doi.org/10.1002/cmdc.201200318
  18. Mellini, P., Kokkola, T., Suuronen, T., Salo, H. S., Tolvanen, L., Mai, A., Lahtela-Kakkonen, M. and Jarho, E. M. (2013) Screen of pseudopeptidic inhibitors of human sirtuins 1-3: two lead compounds with antiproliferative effects in cancer cells. J. Med. Chem. 56, 6681-6695. https://doi.org/10.1021/jm400438k
  19. O'Callaghan, C. and Vassilopoulos, A. (2017) Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 16, 1208-1218. https://doi.org/10.1111/acel.12685
  20. Park, E. Y., Woo, Y., Kim, S. J., Kim, D. H., Lee, E. K., De, U., Kim, K. S., Lee, J., Jung, J. H., Ha, K. T., Choi, W. S., Kim, I. S., Lee, B. M., Yoon, S., Moon, H. R. and Kim, H. S. (2016) Anticancer effects of a new SIRT inhibitor, MHY2256, against human breast cancer MCF-7 cells via regulation of MDM2-p53 binding. Int. J. Biol. Sci. 12, 1555-1567. https://doi.org/10.7150/ijbs.13833
  21. Peck, B., Chen, C. Y., Ho, K. K., Di Fruscia, P., Myatt, S. S., Coombes, R. C., Fuchter, M. J., Hsiao, C. D. and Lam, E. W. (2010) SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol. Cancer Ther. 9, 844-855. https://doi.org/10.1158/1535-7163.MCT-09-0971
  22. Rotili, D., Tarantino, D., Nebbioso, A., Paolini, C., Huidobro, C., Lara, E., Mellini, P., Lenoci, A., Pezzi, R., Botta, G., Lahtela-Kakkonen, M., Poso, A., Steinkühler, C., Gallinari, P., De Maria, R., Fraga, M., Esteller, M., Altucci, L. and Mai, A. (2012) Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells. J. Med. Chem. 55, 10937-10947. https://doi.org/10.1021/jm3011614
  23. Takahashi-Yanaga, F. and Sasaguri, T. (2008) GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell. Signal. 20, 581-589. https://doi.org/10.1016/j.cellsig.2007.10.018
  24. Villalba, J. M. and Alcain, F. J. (2012) Sirtuin activators and inhibitors. Biofactors 38, 349-359. https://doi.org/10.1002/biof.1032
  25. Wang, T., Xu, Z., Lu, Y., Shi, J., Liu, W., Zhang, C., Jiang, Z., Qi, B. and Bai, L. (2019) Recent progress on the discovery of Sirt2 inhibitors for the treatment of various cancers. Curr. Top. Med. Chem. 19, 1051-1058. https://doi.org/10.2174/1568026619666190510103416
  26. Yanar, K., Simsek, B. and Cakatay, U. (2019) Integration of melatonin related redox homeostasis, aging, and circadian rhythm. Rejuvenation Res. 22, 409-419. https://doi.org/10.1089/rej.2018.2159
  27. Zhang, Y., Anoopkumar-Dukie, S., Arora, D. and Davey, A. K. (2020) Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases. Eur. J. Pharmacol. 867, 172847. https://doi.org/10.1016/j.ejphar.2019.172847
  28. Zhou, Z., Ma, T., Zhu, Q., Xu, Y. and Zha, X. (2018) Recent advances in inhibitors of sirtuin1/2: an update and perspective. Future Med. Chem. 10, 907-934. https://doi.org/10.4155/fmc-2017-0207

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