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Induction of Endonucleolytic DNA Cleavage in Human Acute Myelogenous Leukemia Cells by Etoposide, Camptothecin, and Other Cytotoxic Anticancer Drugs: A Cautionary Note¹

Oncology Center, Johns Hopkins Hospital, and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Treatment of human HL-60 or KG1A leukemia cells with the topoisomerase II inhibitor etoposide resulted in extensive DNA degradation. When DNA integrity was analyzed by agarose gel electrophoresis, a nucleosomal ladder became evident 1.5–2 h after addition of etoposide to cells, increased in intensity over 6 h, and persisted at 24 h. Six h after addition of the drug, 94 ± 4% of the cells excluded trypan blue even though as much as 90% of the DNA had been degraded to oligosomal fragments. Exposure of cells to 10 µg/ml (17 µM) etoposide for as little as 45 min was sufficient to induce this DNA damage 4 h later. Preincubation with dinitrophenol abolished the effect of etoposide, suggesting that an energy-requiring step occurred prior to or during the endonucleolytic cleavage. In contrast, the effect of etoposide was not prevented by preincubation of HL-60 cells with the RNA synthesis inhibitor 5,6-dichloro-1-ß-ribofuranosylbenzimidazole or the protein synthesis inhibitors cycloheximide or puromycin. On the contrary, high concentrations of 5,6-dichloro-1-ß-ribofuranosylbenzimidazole, cycloheximide, or puromycin by themselves induced the same endonucleolytic cleavage, as did a variety of diverse cytotoxic agents, including camptothecin (0.1 µM), colcemid (0.1 µg/ml), cis-platinum (20 µM), methotrexate (1 µM), and 1-ß-D-arabinofuranosylcytosine (3 µM). These results suggest that endonucleolytic DNA damage by a preexisting cellular enzyme occurs soon after treatment of HL-60 cells with any of a variety of cytotoxic agents. The observation that a variety of nuclear proteins [including poly(ADP-ribose) polymerase, lamin B, topoisomerase I, topoisomerase II, and histone H1] are degraded concomitant with the DNA fragmentation calls into question the selectivity of the degradative process for DNA. The implications of these results for (a) current theories which focus upon endonucleolytic damage of DNA as a critical early event during cell death, and (b) use of topoisomerase-directed drugs to map topoisomerase-binding sites in active chromatin are discussed.

¹ This work was supported in part by grants from the American Cancer Society (Maryland Division), The Andrew Mellon Foundation, and by Grant CA 06973 from the NIH.

² To whom requests for reprints should be addressed, at Oncology 1-127, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21205.

Received 3/ 1/89. Revised 5/15/89. Accepted 7/13/89.

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				D. K. Perry, M. J. Smyth, H. R. Stennicke, G. S. Salvesen, P. Duriez, G. G. Poirier, and Y. A. Hannun Zinc Is a Potent Inhibitor of the Apoptotic Protease, Caspase-3. A NOVEL TARGET FOR ZINC IN THE INHIBITION OF APOPTOSIS J. Biol. Chem., July 25, 1997; 272(30): 18530 - 18533. [Abstract] [Full Text] [PDF]

				A. A. A. M. D.-V. Oorschot, D. F. Fischer, J. M. Grimbergen, B. Klein, S.-M. Zhuang, J. H. F. Falkenburg, C. Backendorf, P. H. A. Quax, A. J. Van der Eb, and M. H. M. Noteborn Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells PNAS, May 27, 1997; 94(11): 5843 - 5847. [Abstract] [Full Text] [PDF]

				N. L. Harvey, A. J. Butt, and S. Kumar Functional Activation of Nedd2/ICH-1 (Caspase-2) Is an Early Process in Apoptosis J. Biol. Chem., May 16, 1997; 272(20): 13134 - 13139. [Abstract] [Full Text] [PDF]

				Y. A. Hannun Apoptosis and the Dilemma of Cancer Chemotherapy Blood, March 15, 1997; 89(6): 1845 - 1853. [Full Text] [PDF]

				S. H. Kaufmann, P. A. Svingen, S. D. Gore, D. K. Armstrong, Y.-C. Cheng, and E. K. Rowinsky Altered Formation of Topotecan-Stabilized Topoisomerase I-DNA Adducts in Human Leukemia Cells Blood, March 15, 1997; 89(6): 2098 - 2104. [Abstract] [Full Text] [PDF]

				L. M. Martins, T. Kottke, P. W. Mesner, G. S. Basi, S. Sinha, N. Frigon Jr., E. Tatar, J. S. Tung, K. Bryant, A. Takahashi, et al. Activation of Multiple Interleukin-1beta Converting Enzyme Homologues in Cytosol and Nuclei of HL-60 Cells during Etoposide-induced Apoptosis J. Biol. Chem., March 14, 1997; 272(11): 7421 - 7430. [Abstract] [Full Text] [PDF]

				H. Seimiya, T. Mashima, M. Toho, and T. Tsuruo c-Jun NH2-terminal Kinase-mediated Activation of Interleukin-1beta Converting Enzyme/CED-3-like Protease during Anticancer Drug-induced Apoptosis J. Biol. Chem., February 14, 1997; 272(7): 4631 - 4636. [Abstract] [Full Text] [PDF]

				R. Datta, H. Kojima, D. Banach, N. J. Bump, R. V. Talanian, E. S. Alnemri, R. R. Weichselbaum, W. W. Wong, and D. W. Kufe Activation of a CrmA-insensitive, p35-sensitive Pathway in Ionizing Radiation-induced Apoptosis J. Biol. Chem., January 17, 1997; 272(3): 1965 - 1969. [Abstract] [Full Text] [PDF]

				P. Zhou, L. Qian, K. M. Kozopas, and R. W. Craig Mcl-1, a Bcl-2 Family Member, Delays the Death of Hematopoietic Cells Under a Variety of Apoptosis-Inducing Conditions Blood, January 15, 1997; 89(2): 630 - 643. [Abstract] [Full Text] [PDF]

				Q. Song, T. Wei, S. Lees-Miller, E. Alnemri, D. Watters, and M. F. Lavin Resistance of actin to cleavage during apoptosis PNAS, January 7, 1997; 94(1): 157 - 162. [Abstract] [Full Text] [PDF]

				L. Casciola-Rosen and A. Rosen Ultraviolet light-induced keratinocyte apoptosis: A potential mechanism for the induction of skin lesions and autoantibody production in LE Lupus, January 1, 1997; 6(2): 175 - 180. [Abstract] [PDF]

				A. Takahashi, P.-Y. Musy, L. M. Martins, G. G. Poirier, R. W. Moyer, and W. C. Earnshaw CrmA/SPI-2 Inhibition of an Endogenous ICE-related Protease Responsible for Lamin A Cleavage and Apoptotic Nuclear Fragmentation J. Biol. Chem., December 20, 1996; 271(51): 32487 - 32490. [Abstract] [Full Text] [PDF]

				M. Mandal, S. B. Maggirwar, N. Sharma, S. H. Kaufmann, S.-C. Sun, and R. Kumar Bcl-2 Prevents CD95 (Fas/APO-1)-induced Degradation of Lamin B and Poly(ADP-ribose) Polymerase and Restores the NF-kappa B Signaling Pathway J. Biol. Chem., November 29, 1996; 271(48): 30354 - 30359. [Abstract] [Full Text] [PDF]

				P. Lassota, G. Singh, and R. Kramer Mechanism of Topoisomerase II Inhibition by Staurosporine and Other Protein Kinase Inhibitors J. Biol. Chem., October 18, 1996; 271(42): 26418 - 26423. [Abstract] [Full Text] [PDF]

				T. Nakajima, K. Morita, N. Ohi, T. Arai, N. Nozaki, A. Kikuchi, F. Osaka, F. Yamao, and K. Oda Degradation of Topoisomerase IIalpha during Adenovirus E1A-induced Apoptosis Is Mediated by the Activation of the Ubiquitin Proteolysis System J. Biol. Chem., October 4, 1996; 271(40): 24842 - 24849. [Abstract] [Full Text] [PDF]

				DavidJ. McConkey and D. J. McConkey Calcium-dependent, Interleukin 1beta -converting Enzyme Inhibitor-insensitive Degradation of Lamin B1 and DNA Fragmentation in Isolated Thymocyte Nuclei J. Biol. Chem., September 13, 1996; 271(37): 22398 - 22406. [Abstract] [Full Text] [PDF]

				M. Watabe, Y. Masuda, S. Nakajo, T. Yoshida, Y. Kuroiwa, and K. Nakaya The Cooperative Interaction of Two Different Signaling Pathways in Response to Bufalin Induces Apoptosis in Human Leukemia U937 Cells J. Biol. Chem., June 14, 1996; 271(24): 14067 - 14073. [Abstract] [Full Text] [PDF]

				Y. S. Yoon, J. W. Kim, K. W. Kang, Y. S. Kim, K. H. Choi, and C. O Joe Poly(ADP-ribosyl)ation of Histone H1 Correlates with Internucleosomal DNA Fragmentation during Apoptosis J. Biol. Chem., April 12, 1996; 271(15): 9129 - 9134. [Abstract] [Full Text] [PDF]

				M. Fraser, S. Tynan, A Papaioannou, C. Ireland, and S. Pittman Endo-exonuclease of human leukaemic cells: evidence for a role in apoptosis J. Cell Sci., January 9, 1996; 109(9): 2343 - 2360. [Abstract] [PDF]

				V. Weaver, C. Carson, P. Walker, N Chaly, B Lach, Y Raymond, D. Brown, and M Sikorska Degradation of nuclear matrix and DNA cleavage in apoptotic thymocytes J. Cell Sci., January 1, 1996; 109(1): 45 - 56. [Abstract] [PDF]

				S. Tawfic, M. O. J. Olson, and K. Ahmed Role of Protein Phosphorylation in Post-translational Regulation of Protein B23 during Programmed Cell Death in the Prostate Gland J. Biol. Chem., September 8, 1995; 270(36): 21009 - 21015. [Abstract] [Full Text] [PDF]

				M. Tewari, D. R. Beidler, and V. M. Dixit CrmA-inhibitable Cleavage of the 70-kDa Protein Component of the U1 Small Nuclear Ribonucleoprotein during Fas- and Tumor Necrosis Factor-induced Apoptosis J. Biol. Chem., August 11, 1995; 270(32): 18738 - 18741. [Abstract] [Full Text] [PDF]

				S. D. Patterson, J. S. Grossman, P. D'Andrea, and G. I. Latter Reduced Numatrin/B23/Nucleophosmin Labeling in Apoptotic Jurkat T-lymphoblasts J. Biol. Chem., April 21, 1995; 270(16): 9429 - 9436. [Abstract] [Full Text] [PDF]