Abstract
The cytotoxic effect of the anticancer drug doxorubicin (DR) on human embryonic stem cells (ESCs) C910 and fibroblasts spontaneously differentiated from these cells has been examined. The fibroblasts retained a diploid karyotype. It was found that ESCs are more sensitive to DR than fibroblasts: the DR dose killing 20% of cells was 0.01 and 0.1 μg/mL, respectively. DR induced ESC apoptotic death and reduced both ESC and fibroblast proliferation. DR reversibly inhibited ESC, but not fibroblast, proliferation. Thus, we demonstrated that ESCs and differentiated derivatives thereof are distinguished by sensitivity and response to the genotoxic agent.
Similar content being viewed by others
References
Burden, D.A. and Osheoff, N., Mechanism of Action of Eukaryotic Topoisomerase II and Drugs Targeted to the Enzyme, Biochim. Biophys. Acta, 1998, vol. 1400, pp. 139–154.
Eom, Y.W., Kim, M.A., Park, S.S., Goom, J., Sohn, S., Kim, W.H., Yoon, G., and Choi, K.S., Two Distinct Modes of Cell Death Induced by Doxorubicin: Apoptosis and Cell Death through Mitotic Catastrophe Accompanied by Senescence-Like Phenotype, Oncogene, 2005, vol. 24, pp. 4765–4777.
Filion, T.M., Qiao, M., Ghule, P.N., Mandeville, M., Wijnen, A.J., Stein, J.L., Lian, J.B., Altieri, D.C., and Stein, G.S., Survival Responses of Human Embryonic Stem Cells to DNA Damage, J. Cell Physiol., 2009, vol. 220, pp. 586–592.
Grandela, C., Pera, M.F., and Wolvetang, E.J., p-53 Is Required for Etoposide-Induced Apoptosis of Human Embryonic Stem Cells, Stem Cell Res., 2007, vol. 1, pp. 116–128.
Kikuchi, I., Nakayama, Y., Morinaga, T., Fukumoto, Y., and Yamaguchi, N., A Decrease in Cyclin B1 Levels Leads to Polyploidization in DNA Damage-Induced Senescence, Cell Biol. Int., 2010, vol. 34, pp. 645–653.
Kim, H.-S., Lee, Y.-S., and Kim, D.-K., Doxorubicin Exerts Cytotoxic Effects through Cell Cycle Arrest and Fas-Mediated Cell Death, Pharmacology, 2009, vol. 84, pp. 300–309.
Kozhukharova, I.V., Fridlyanskaya, I.I., Kovaleva, Z.V., Pugovkina, N.A., Alekseenko, L.L., Zenin, V.V., Ivantsov, K.M., Leont’eva, O.K., Grinchuk, T.M., and Nikolsky, N.N., Novel Human Embryonic Stem Cell Lines C612 and C910, Cell Tiss. Biol., 2009, vol. 3, no. 6, pp. 519–526.
Mamaeva, S.E., Atlas khromosom postoyannykh kletochnykh linii cheloveka i zhivotnykh (Atlas of Chromosomes of Permanent Human and Animal Cell Lines), Moscow: Nauka, 2002.
Maynard, A., Swistowska, A.M., Lee, J.W., Liu, Y., Liu, S., Da Cruz, A.B., Rao, M., Souza-Pinto, N., Zeng, X., and Bohr, V., Human Embryonic Stem Cells Have Enhanced Repair of Multiple Forms of DNA Damage, Stem Cells, 2008, vol. 26, pp. 2266–2274.
Meliksityan, M.B., Berezkina, E.V., Pavlenko, M.A., and Grinchuk, T.M., Mechanisms of Drug Resistance of Two Cell Lines of Human Chronic Promyelocytic Leukemia K562, Resistant to DNA Topoisomerase II Inhibitors Adriamycin and Etoposide, Tsitologiia, 1999, vol. 41, no. 7, pp. 615–621.
Neganova, I., Vilella, F., Atkinson, S.P., Lloret, M., Passos, J.F., Zglincki, T., O’Connor, J.-E., Burks, D., Jones, R., Armstrong, L., and Lako, M., An Important Role for CDK2 in G1 to S Checkpoint Activation and DNA Damage Response in Human Embryonic Stem Cells, Stem Cells, 2011, vol. 29, pp. 651–659.
Rebbaa, A., Zheng, X., Chou, P.M., and Mirkin, B.L., Caspase Inhibition Switches Doxorubicin-Induced Apoptosis to Senescence, Oncogene, 2003, vol. 22, pp. 2805–2811.
Saretzki, G., Walter, T., Atkinson, S., Passos, J.F., Breth, B., Keith, W.N., Stewart, R., Hoare, S., Stojkovic, M., Armstrong, L., Zglinicki, T., and Lako, M., Downregulation of Multiple Stress Defense Mechanisms during Differentiation of Human Embryonic Stem Cells, Stem Cells, 2008, vol. 26, pp. 455–464.
Tsang, W.P., Chau, S.P., Kong, S.K., Fung, K.P., and Kwok, T.T., Reactive Oxygen Species Mediate Doxorubicin Induced p53-Independent Apoptosis, Life Sci., 2003, vol. 73, pp. 2047–2058.
Velichko, A.K., Lagarkova, M.A., Philonenko, E.S., Kiselev, S.L., Katidze, O.L., and Rasin, S.V., Sensitivity of Human Embryonic and Induced Pluripotent Stem Cells to a Topoisomerase II Poison Etoposide, Cell Cycle, 2011, vol. 10, pp. 2035–2037.
Wang, S., Konorev, E.A., Kotamraju, S., Joseph, J., Kolivendi, S., and Kalyanaraman, B., Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms, Intermediacy of H(2)O(2)- and p-53-Dependent Pathways, J. Biol. Chem., 2004, vol. 279, pp. 25536–25543.
Wang, X., Watt, P., Louis, R.H., and Hickson, I.D., Part I: A Topoisomerase II-Associated Protein Required for Faithful Chromosome Transmission in Saccharomyces cerevisiae, Nucl. Acids Res., 1996, vol. 24, pp. 4791–4797.
Yunis, J.J., Nomenclature for High Resolution Human Chromosomes, Cancer Genet. Cytogenet., 1980, vol. 2, pp. 221–229.
Zemelko, V.I., Grinchuk, T.M., Domnina, A.P., Artsybasheva, I.V., Zenin, V.V., Kirsanov, A.A., Bichevaya, N.K., Korsak, V.S., and Nikolsky, N.N., Multipotent Mesenchymal Stem Cells of Desquamated Endometrium: Isolation, Characterization, and Application as a Feeder Layer for Maintenance of Human Embryonic Stem Cells, Cell Tiss. Biol., 2012, vol. 6, no. 1, pp. 1–11.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © I.V. Kozhukharova, T.M. Grinchuk, N.A. Pugovkina, Z.V. Kovaleva, L.L. Alekseenko, N.N. Nikolskiy, 2012, published in Tsitologiya, 2012, Vol. 54, No. 10, pp. 761–766.
Rights and permissions
About this article
Cite this article
Kozhukharova, I.V., Grinchuk, T.M., Pugovkina, N.A. et al. Cytotoxicity of the anticancer drug doxorubicin for human embryonic stem cells. Cell Tiss. Biol. 7, 15–20 (2013). https://doi.org/10.1134/S1990519X13010100
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X13010100