Cell cycle arrest effect of compound YSY-01A, a new proteasome inhibitor, on HT-29 cells in vitro

doi:10.5246/jcps.2012.05.059

Abstract

Abstract: Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29. The results suggested that YSY-01A significantly (P<0.05) inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner. Furthermore, YSY-01A suppressed the G₂/M transition of HT-29 cells, whereas the mitotic inhibitor paclitaxel induced M phase accumulation. Further investigation revealed that YSY-01A significantly (P<0.05) up-regulated the expression levels of a series of cell cycle related protein, such as cyclin B1, Wee1, p-cdc2 (Tyr15), p53, p21, and p27. The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM (P<0.05), which was above the dose we used in the mechanism research. In conclusion, YSY-01A showed remarkable anti-cancer activity on HT-29 cells, and its molecular mechanisms are related to G₂/M cell cycle transition arrest.

Key words: Proteasome inhibitor, YSY-01A, HT-29, Cell-cycle related protein, HCS

CLC Number:

R965

Supporting:

Kan Tong, Jingtao Liu, Xia Yuan, Bo Xu, Wei Guo, Liqiang Han, Shuyang Yao, Zemei Ge, Runtao Li^*, Jingrong Cui^*. Cell cycle arrest effect of compound YSY-01A, a new proteasome inhibitor, on HT-29 cells in vitro[J]. , DOI: 10.5246/jcps.2012.05.059.

References

[1] Grimm, L.M.; Goldberg, A.L.; Poirier, G.G.; Schwartz, L.M.; Osborne, B.A. EMBO J. 1996, 15, 3835-3844.
[2] Roccaro, A.M.; Hideshima, T.; Raje, N.; Kumar, S.; Ishitsuka, K.; Yasui, H.; Shiraishi, N.; Ribatti, D.; Nico, B.; Vacca. A.; Dammacco, F.; Richardson, P.G.; Anderson, K.G. Cancer Res. 2006, 66, 184-191.
[3] Rajkumar, S.V.; Richardson, P.G.; Hideshima, T.; Anderson, K.C. J. Clin. Oncol. 2005, 23, 630-639.
[4] Mani, A.; Gelmann, E.P. J. Clin. Oncol. 2005, 23, 4776-4789.
[5] Boyette-Davis, J.A.; Cata, J.P.; Zhang, H.; Driver, L.C.; Wenderlschafer-Crabb, G.; Kennedy, W.R.; Dougherty, P.M. J. Pain. 2011, 12, 1017-1024.
[6] Kropff, M.; Bisping, G.; Wenning, D.; Berdel, W.E.; Kienast, J. Eur. J. Cancer. 2006, 42, 1623-1639.
[7] Jung, L.; Holle, L.; Dalton, W.S. Oncology (Williston Park). 2004, 18, 4-13.
[8] Richardson, P.G.; Sonneveld, P.; Schuster, M.W.; David, I.; Edward, A.S.; Thierry, F.; Harousseau, J.L.; Ben-Yehuda, D.; Lonial, S.; Goldschmidt, H.; Reece, D.; San-Miguel, J.F.; Bladé, J.; Boccadoro, M.; Cavenagh, J.; Dalton, W.S.; Boral, A.L.; Esseltine, D.L.; Porter, J.B.; Schenkein, D.; Anderson, K.C. N. Engl. J. Med. 2005, 352, 2487-2498.
[9] Shao, R.G.; Cao, C.X.; Shimizu, T.; O'Connor, P.M.; Kohn, K.W.; Pommier, Y. Cancer Res. 1997, 57, 4029-4035.
[10] Stewart, Z.A.; Westfall, M.D.; Pietenpol, J.A. Trends Parmacol. Sci. 2003, 24, 139-145.
[11] Will, R. Rev. Undergraduate Res. 2002, 1, 1-7.
[12] Charles, J.S. Cancer Res. 2000, 60, 3689-3695.
[13] Elledge, S.J. Science. 1996, 274, 1664-1672.
[14] O'Connor, P.M. Cancer Surv. 1997, 29, 151-182.
[15] Gasparri, F.; Cappella, P.; Galvani, A. J. Biomol. Screen. 2006, 11, 586-598.
[16] Castedo, M.; Perfettini, J.L.; Roumier, T.; Kroemer, G. Cell Death Differ. 2002, 9, 1287-1293.
[17] Clute, P.; Pines, J. Nat. Cell Biol. 1999, 1, 82-87.
[18] Fry, A.M.; Yamano, H. Cell Cycle. 2006, 5, 1487-1491.
[19] Connell, M.; Walworth, N.; Carr, A.M. Trends Cell Biol. 2000, 10, 296-303.
[20] Yan, X.L.; Xu, B.; Li, M.; Zhou, Y.; Cui, J.R. Chin. Pharm. J. 2009, 44, 904-908.
[21] Michael, W.M.; Newport, J. Science. 1998, 282, 1886-1889.
[22] Taylor, W.R.; Stark, G.R. Oncogene. 2001, 20, 1803-1815.
[23] Weng, M.S.; Ho, Y.S.; Lin, J.K. Biochem. Pharmacol. 2005, 69, 1815-1827.
[24] Sun, S.Y.; Yue, P.; Wu, G.S.; EI-Deiry, W.S.; Shroot, B.; Hong, W.K.; Lotan, R. Cancer Res. 1999, 59, 2829-2833.
[25] Tsvetkov, L.M.; Yeh, K.H.; Lee, S.J.; Sun, H.; Zhang, H. Curr. Biol. 1999, 9, 661-664.
[26] Blagosklonny, M.V.; Wu, G.S.; Omura, S.; El-Deiry, W.S. Biochem. Biophys. Res. Commun. 1996, 227, 564-569.
[27] Jentsch, S. Trends Cell Biol. 1992, 2, 98-103.
[28] Clahsen, P.C.; van de Velde, C.J.; Duval, C.; Pallud, C.; Mandard, A.M.; Delobelle-Deroide, A.; van den Broek, L.; van de Vijver, M.J. Eur. J. Surg. Oncol. 1999, 25, 356-363.
[29] Sinicrope, F.A.; Hart, J.; Hsu, H.A.; Lemoine, M.; Michelassi, F.; Stephens, L.C. Clin. Cancer Res. 1999, 5, 1793-1804.