Natural polyamine is an ideal antitumor drug carrier because of the great requirement difference between cancer cells and normal cells. Previous data demonstrated that many cytotoxic drugs conjugated with natural or synthetic polyamines have potent antitumor effects. Up to now, the antitumor mechanism of conjugates of naphthalimides with polyamine remains poorly understood in human colon cancer cells. The aim of this study is to evaluate the effect of MINS (a novel naph-thalimide-polyamine conjugate) and mechanism of MINS in human colon cancer cells. Mitochondrial toxicity, which was generated by ROS from mitochondria electron transport chain, might be a major factor in MINS-inducted apoptosis. Our data also demonstrated that MINS-mediated cell apoptosis depend on p53 status, for MINS induced Caco-2 cells (p53 null) only necrosis but not apoptosis. Furthermore, the apoptotic effect of MINS is stronger than that of Amonafide, the parent drug of MINS. Our data suggested that the MINS-mediated cell apoptosis depend on p53 in human colon cancer cells.
References
[1]
Cantero-Munoz, P., Urién, M.A. and Ruano-Ravina, A. (2011) Efficacy and Safety of Intraoperative Radiotherapy in Colorectal Cancer: A Systematic Review. Cancer Letters, 306, 121-133. http://dx.doi.org/10.1016/j.canlet.2011.02.020
[2]
Nelson, S.M., Ferguson, L.R. and Denny, W.A. (2004) DNA and the Chromosome-Varied Targets for Chemotherapy. Cell Chromosome, 3, 2. http://dx.doi.org/10.1186/1475-9268-3-2
[3]
Brana, M.F. and Ramos, A. (2001) Naphthalimides as Anticancer Agents: Synthesis and Biological Activity. Current Medicinal Chemistry-Anti-Cancer Agents, 1, 237-255. http://dx.doi.org/10.2174/1568011013354624
[4]
Nasizadeh, S., Myhre, L., Thiman, L., Alm, K., Oredsson, S. and Persson, L. (2005) Importance of Polyamines in Cell Cycle Kinetics as Studied in a Transgenic System. Experimental Cell Research, 308, 254-264.
http://dx.doi.org/10.1016/j.yexcr.2005.04.027
[5]
Basuroy, U.K. and Gerner, E.W. (2006) Emerging Concepts in Targeting the Polyamine Metabolic Pathway in Epithelial Cancer Chemoprevention and Chemotherapy. Journal of Biochemistry, 139, 27-33.
http://dx.doi.org/10.1093/jb/mvj022
[6]
Tian, Z.Y., Ma, H.X., Xie, S.Q., Wang, X. and Zhao, J. (2008) Synthesis, DNA Binding and Topoisomerase Inhibition of Mononaphthalimide Homospermidine Derivatives. Chinese Chemical Letters, 19, 509-512.
http://dx.doi.org/10.1016/j.cclet.2008.03.006
[7]
Xie, S., Wang, J., Zhang, Y. and Wang, C. (2010) Antitumor Conjugates with Polyamine Vectors and Their Molecular Mechanisms. Expert Opinion on Drug Delivery, 7, 1049-1061. http://dx.doi.org/10.1517/17425247.2010.504205
[8]
Xie, S.Q., Li. Q., Zhang, Y.H., Wang, J.H., Mei, Z.H., Zhao, J. and Wang, C. (2011) NPC-16, a Novel Naphthalimide-Polyamine Conjugate, Induced Apoptosis and Autophagy in Human Hepatoma HepG2 Cells and Bel-7402 Cells. Apoptosis, 16, 27-34. http://dx.doi.org/10.1007/s10495-010-0537-1
[9]
Wang, Y., Zhang, X., Zhao, J., Xie, S. and Wang, C. (2012) Nonhematotoxic Naphthalene Diimide Modified by Polyamine: Synthesis and Biological Evaluation. Journal of Medicinal Chemistry, 55, 3502-3512.
http://dx.doi.org/10.1021/jm300168w
[10]
Xie, S.Q., Wu, Y.L., Cheng, P.F., Wang, M.W., Liu, G.C., Ma, Y.F., Zhao, J. and Wang, C.J. (2007) A Novel Homospermidine Conjugate Inhibits Growth and Induces Apoptosis in Human Hepatoma Cells. Acta Pharmacologica Sinica, 28, 1827-1834. http://dx.doi.org/10.1111/j.1745-7254.2007.00639.x
[11]
Brana, M.F., Cacho, M., García, M.A., de Pascual-Teresa, B., Ramos, A., Acero, N., Llinares, F., Munoz-Mingarro, D., Abradelo, C., Rey-Stolle, M.F. and Yuste, M. (2002) Synthesis, Antitumor Activity, Molecular Modeling and DNA Binding Properties of a New Series of Imidazonaphthalimides. Journal of Medicinal Chemistry, 45, 5813-5816.
http://dx.doi.org/10.1021/jm020950q
[12]
Tian, Z.Y., Xie, S.Q., Mei, Z.H., Zhao, J., Gao, W.Y. and Wang, C.J. (2009) Conjugation of Substituted Naphthalimides to Polyamines as Cytotoxic Agents Targeting the Akt/mTOR Signal Pathway. Organic Biomolecular Chemistry, 7, 4651-4660. http://dx.doi.org/10.1039/b912685f
[13]
Tian, Z.Y., Xie, S.Q., Du, Y.W., Ma, Y.F., Zhao, J., Gao, W.Y. and Wang, C.J. (2009) Synthesis, Cytotoxicity and Apoptosis of Naphthalimide Polyamine Conjugates as Antitumor Agents. European Journal of Medicinal Chemistry, 44, 393-399. http://dx.doi.org/10.1016/j.ejmech.2008.02.044
[14]
Xie, S.Q., Li, Q., Zhang, Y.H., Wang, J.H., Zhao, J. and Wang, C.J. (2010) NNINspm, Naphthalimide-Polyamine Conjugate, Induces Hepatoma HepG2 Cell Apoptosis via PI3K/Akt Pathways. Chinese Pharmacological Bulletin, 26,169-174.
[15]
Wasilewski, M. and Scorrano, L. (2009) The Changing Shape of Mitochondrial Apoptosis. Trends in Endocrinology Metabolism, 20, 287-294. http://dx.doi.org/10.1016/j.tem.2009.03.007
[16]
Circu, M.L. and Aw, T.Y. (2010) Reactive Oxygen Species, Cellular Redox Systems and Apoptosis. Free Radical Biology Medicine, 48, 749-762. http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.022
[17]
Shen, K., Sun, L., Zhang, H., Xu, Y., Qian, X., Lu, Y., Li, Q., Ni, L. and Liu, J. (2013) A ROS-Mediated Lysosomal-Mitochondrial Pathway Is Induced by a Novel Amonafide Analogue, 7c, in Human Hela Cervix Carcinoma Cells. Cancer Letters, 333, 229-238. http://dx.doi.org/10.1016/j.canlet.2013.01.038
[18]
Yang, L., Zhao, J., Zhu, Y., Tian, Z. and Wang, C. (2011) Reactive Oxygen Species (ROS) Accumulation Induced by Mononaphthalimide-Spermidine Leads to Intrinsic and AIF-Mediated Apoptosis in Hela Cells. Oncology Reports, 25, 1099-1107. http://dx.doi.org/10.3892/or.2011.1173
[19]
Gonmes, N.P. and Espinosa, J.M. (2010) Gene-Specific Repression of the p53 Target Gene PUMA via Intragenic CTCF-Cohesin Binding. Genes Development, 24, 1022-1034. http://dx.doi.org/10.1101/gad.1881010
[20]
Al-Hai, L., Blackshear, P.J. and Khabar, K.S. (2012) Regulation of p21/CIP1/WAF-1 Mediated Cell-Cycle Arrest by RNase L and Tristetraprolin and Involvement of AU-Rich Elements. Nucleic Acids Research, 40, 7739-7752.
http://dx.doi.org/10.1093/nar/gks545
