Abstract
Histone deacetylase inhibitors (HDIs) cause an irreversible cell cycle arrest in G1 phase and senescence of E1A + Ras transformed fibroblasts. The modulation of the antiproliferative action of the RNA synthesis inhibitor actinomycin D (AMD) with sodium butyrate (NaBut) has been studied. It is shown that NaBut enhances the cytotoxic effect of low AMD concentrations (<8 nM). However, at high concentrations of AMD, NaBut increases E1A + Ras cell viability insignificantly. At low concentrations of AMD, NaBut dramatically reduces the clonogenic ability of transformed cells and increases their death. The study of the mechanisms of cell death induced by combined action of low AMD concentrations and NaBut showed that combined exposure led to activation of the p53 proapoptotic transcription factor and suppression of the NF-κΒ antiapoptotic factor activity. Thus, NaBut enhances the cytotoxic effect of low AMD concentrations on oncogene-transformed cells, enhancing their apoptotic death. These results can be used in the selection of the optimal combination of AMD and HDIs in combination therapy of tumors.
Similar content being viewed by others
Abbreviations
- AMD:
-
actinomycin D
- HDIs:
-
histone deacetylase inhibitors
- NaBut:
-
sodium butyrate
References
Abramova, M.V., Pospelova, T.V., Nikulenkov, F.P., Hollander, C.M., Fornace, A.J., and Pospelov, V.A., G1/S arrest induced by histone deacetylase inhibitor sodium butyrate in E1A + Ras-transformed cells is mediated through down-regulation of E2F activity and stabilization of beta-catenin, J. Biol. Chem., 2006, vol. 281, pp. 21040–21051.
Abramova, M.V., Zatulovskiy, E.A., Svetlikova, S.B., and Pospelov, V.A., HDAC inhibitor-induced activation of NF-B prevents apoptotic response of E1A + Ras-transformed cells to proapoptotic stimuli, Int. J. Biochem. Cell. Biol., 2010, vol. 42, pp. 1847–1855.
Abramova, M.V., Svetlikova, S.B., Kukushkin, A.N., Aksenov, N.D., Pospelova, T.V., and Pospelov, V.A., HDAC inhibitor sodium butyrate sensitizes E1A + Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of ?H2AX foci, Cancer Biol. Ther., 2011, vol. 12, pp. 1069–1077.
Ashcroft, M., Kubbutat, M.H., and Vousden, K.H., Regulation of p53 function and stability by phosphorylation, Mol. Cell. Biol., 1999, vol. 19, pp. 1751–1758.
Ashcroft, M., Taya, Y., and Vousden, K.H., Stress signals utilize multiple pathways to stabilize p53, Mol. Cel. Biol., 2000, vol. 20, pp. 3224–3233.
Beagle, B.R., Nguyen, D.M., Mallya, S., Tang, S.S., Lu, M., Zeng, Z., Konopleva, M., Vo, T.T., and Fruman, D.A., mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells, Oncotarget, 2015, vol. 6, pp. 2088–2100.
Blagosklonny, M.V., P53: an ubiquitous target of anticancer drugs, Int. J. Cancer, 2002, vol. 98, pp. 161–166.
Blagosklonny, M.V. and Darzynkiewicz, Z., Cyclotherapy: protection of normal cells and unshielding of cancer cells, Cell Cycle, 2002, vol. 1, pp. 375–382.
Blagosklonny, M.V. and Pardee, A.B., Exploiting cancer cell cycling for selective protection of normal cells, Cancer Res., 2001, vol. 61, pp. 4301–4305.
Blattner, C., Tobiasch, E., Litfen, M., Rahmsdorf, H.J., and Herrlich, P., DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation, Oncogene, 1999, vol. 18, pp. 1723–1732.
Chen, C.S., Ho, D.R., Chen, F.Y., Chen, C.R., Ke, Y.D., and Su, J.G., AKT mediates actinomycin D-induced p53 expression, Oncotarget, 2014, vol. 5, pp. 693–703.
Chiba, T., Yokosuka, O., Fukai, K., Kojima, H., Tada, M., and Arai, M., Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin a, on human hepatoma cells, Oncology, 2004, vol. 66, pp. 481–491.
Choong, M.L., Yang, H., Lee, M.A., and Lane, D.P., Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy, Cell Cycle, 2009, vol. 8, pp. 2810–2818.
Chung, Y.H., Youn, J., Choi, Y., Paik, D.J., and Cho, Y.J., Requirement of de novo protein synthesis for aminopterininduced apoptosis in a mouse myeloma cell line, Immunol. Lett., 2001, vol. 77, pp. 127–131.
Culmsee, C., Siewe, J., Junker, V., Retiounskaia, M., Schwarz, S., Camandola, S., El-Metainy, S., Behnke, H., Mattson, M.P., and Krieglstein, J., Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons, J. Neurosci., 2003, vol. 23, pp. 8586–8595.
Dong, L.H., Cheng, S., Zheng, Z., Wang, L., Shen, Y., Shen, Z.X., Chen, S.J., and Zhao, W.L., Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma, J. Hematol. Oncol., 2013, vol. 6, p. 53.
Glazyrin, A.L., Chinni, S., Alhasan, S., Adsay, V.N., Vaitkevicius, V.K., and Sarkar, F.H., Molecular mechanism(s) of actinomycin-D induced sensitization of pancreatic cancer cells to CD95 mediated apoptosis, Int. J. Oncol., 2002, vol. 20, pp. 201–205.
Huang, W.C., Ju, T.K., Hung, M.C., and Chen, C.C., Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB, Mol. Cell., 2007, vol. 26, pp. 75–87.
Igotti Abramova, M.V., Pojidaeva, A.K., Filippova, E.A., Gnedina, O.O., Svetlikova, S.B., and Pospelov, V.A., HDAC inhibitors induce apoptosis but not cellular senescence in Gadd45a-deficient E1A + Ras cells, Int. J. Biochem. Cell Biol., 2014, vol. 51, pp. 102–110.
Keyomarsi, K. and Pardee, A.B., Selective protection of normal proliferating cells against the toxic effects of chemotherapeutic agents, Prog. Cell. Cycle Res., 2003, vol. 5, pp. 527–532.
Kim, Y.K., Lee, E.K., Kang, J.K., Kim, J.A., You, J.S., Park, J.H., Seo, D.W., Hwang, J.W., Kim, S.N., Lee, H.Y., Lee, H.W., and Han, J.W., Activation of NF-kappaB by HDAC inhibitor apicidin through Sp1-dependent de novo protein synthesis: its implication for resistance to apoptosis, Cell Death Differ., 2006, vol. 13, pp. 2033–2041.
Liu, X., Chen, H., and Patel, D.J., Solution structure of actinomycin-DNA complexes: drug interaction at isolated G-C sites, J. Biomol. NMR, 1991, vol. 1, pp. 323–347.
Newton, R., Adcock, I.M., and Barnes, P.J., Superinduction of NF-kappa B by actinomycin D and cycloheximide in epithelial cells, Biochem. Biophys. Res. Commun., 1996, vol. 218, pp. 518–523.
Noh, E.J., Lim, D.S., Jeong, G., and Lee, J.S., An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcription-dependent manner, Biochem. Biophys. Res. Commun., 2009, vol. 378, pp. 326–331.
Patel, J., Sullivan, P., Zhang, K., Zhang, S., and Mock, B., Combined use of HDAC and mTOR inhibitors has synergistic effect on inhibiting B-cell tumor cell lines, Mol. Cancer Ther., 2007, vol. 6, p. 139.
Pospelova, T.V., Medvedev, A.V., Kukushkin, A.N., Svetlikova, S.B., van der Eb, A.J., Dorsman, J.C., and Pospelov, V.A., E1A + cHa-ras transformed rat embryo fibroblast cells are characterized by high and constitutive DNA binding activities of AP-1 dimers with significantly altered composition, Gene Expression, 1999, vol. 8, pp. 19–32.
Pospelova, T.V., Leontieva, O.V., Bykova, T.V., Zubova, S.G., Pospelov, V.A., and Blagosklonny, M.V., Suppression of replicative senescence by rapamycin in rodent embryonic cells, Cell Cycle, 2012, vol. 11, pp. 2402–2407.
Qing, C., Miao, Z.H., Tong, L.J., Zhang, J.S., and Ding, J., Actinomycin D inhibiting K562 cell apoptosis elicited by salvicine but not decreasing its cytotoxicity, Acta Pharmacol. Sin., 2003, vol. 24, pp. 415–421.
Ravi, R., Mookerjee, B., van Hensbergen, Y., Bedi, G.C., Giordano, A., El-Deiry, W.S., Fuchs, E.J., and Bedi, A., p53-Mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300, Cancer Res., 1998, vol. 58, pp. 4531–4536.
Ross, W.E. and Bradley, M.O., DNA double-strand breaks in mammalian cells after exposure to intercalating agents, Biochem. Biophys. Acta, 1981, vol. 654, pp. 129–134.
Schrump, D.S., Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications, Clin. Cancer Res., 2009, vol. 15, pp. 3947–3957.
Shang, X., Shiono, Y., Fujita, Y., Oka, S., and Yamazaki, Y., Synergistic enhancement of apoptosis by DNA- and cytoskeleton-damaging agents: a basis for combination chemotherapy of cancer, Anticancer Res., 2001, vol. 4A, pp. 2585–2589.
Shieh, S.-Y., Ikeda, M., Taya, Y., and Prives, C., DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2, Cell, 1997, vol. 91, pp. 325–334.
Shim, D., Kang, H.Y., Jeon, B.W., Kang, S.S., Chang, S.I., and Kim, H.Y., Protein kinase B inhibits apoptosis induced by actinomycin D in ECV304 cells through phosphorylation of caspase 8, Arch. Biochem. Biophys., 2004, vol. 425, pp. 214–220.
Sobell, H.M., Actinomycin and DNA transcription, Proc. Natl. Acad. Sci. U. S. A., 1985, vol. 82, pp. 5328–5331.
Tao, W. and Levine, A.J., p19ARF stabilizes p53 by blocking nucleocytoplasmic shuttling of Mdm2, Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 6937–6941.
van Leeuwen, I.M., Higgins, M., Campbell, J., Brown, C.J., McCarthy, A.R., Pirrie, L., Westwood, N., and Lain, S., Mechanism-specific signatures for smallmolecule p53 activators, Cell Cycle, 2011, vol. 10, pp. 1590–1598.
Weber, J.D., Taylor, L.J., Roussel, M.F., Sherr, C.J., and Bar-Sagi, D., Nucleolar Arf sequesters Mdm2 and activates p53, Nat. Cell Biol., 1999, vol. 1, pp. 20–26.
Webster, G.A. and Perkins, N.D., Transcriptional cross talk between NF-kappaB and p53, Mol. Cell. Biol., 1999, vol. 19, pp. 3485–3495.
Yamada, M., Banno, Y., Takuwa, Y., Koda, M., Hara, A., and Nozawa, Y., Overexpression of phospholipase D prevents actinomycin D-induced apoptosis through potentiation of phosphoinositide 3-kinase signalling pathways in chinese-hamster ovary cells, Biochem. J., 2004, vol. 378, pp. 649–656.
Yu, C. and Tseng, Y.Y., NMR study of the solution confirmation of actinomycin D, Eur. J. Biochem., 1992, vol. 209, pp. 181–187.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © M.V. Igotti, O.O. Gnedina, S.B. Svetlikova, E.A. Filippova, V.A. Pospelov, 2016, published in Tsitologiya, 2016, Vol. 58, No. 10, pp. 755–762.
Rights and permissions
About this article
Cite this article
Igotti, M.V., Gnedina, O.O., Svetlikova, S.B. et al. Sodium butyrate enhances the antiproliferative action of low actinomycin D concentrations. Cell Tiss. Biol. 11, 42–50 (2017). https://doi.org/10.1134/S1990519X17010059
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X17010059