Another, scheduled for Wednesday at noon.
[PROC. AMER. ASSOC. CANCER RES. 40, March 1999]
Copyright © 1999 by the American Association for Cancer Research
#4862 Is drug-induced DNA damage sufficient for apoptosis induction? Woynarowski, J.M.*, Koester, S.K.#, Woynarowska, B.+, Arnett, B.*, Chan, D., Munoz, R.+, Herzig, M.C.S.*, and Faivre, S.* Cancer Therapy and Research Center, San Antonio, TX 78245*, Beckman-Coulter Technology Center, Miami, FL 33196#, and The University of Texas Health Science Center, San Antonio, TX 7878284+.
Drug-induced DNA damage is generally considered an apoptotic stimulus. However, the contribution of protein damage caused by many DNA-reactive drugs seems overlooked. We compared apoptosis in CEM cells by drugs which: bind only to proteins (sulfhydryl crosslinker diamide), bind only to DNA (bizelesin), and bind to both DNA and protein (hydroxymethylacylfulvene [HMAF], oxaliplatin, and cisplatin). The apoptotic effects were related to drug concentrations inhibiting cell growth by 80% (IC80) which amounted to 10-4, 10-12, 5 x 10-6 M, for diamide, bizelesin, and HMAF, respectively, and 25 x 10-6 M for cisplatin and oxaliplatin. Apoptosis was monitored based on cell morphology, apoptotic fragmentation, and multiparametric flow cytometry including markers for early and late apoptosis, strand breaks, and viability. The results show that diamide, HMAF, oxaliplatin, and cisplatin induce apoptosis after 24 h at pharmacologically relevant drug concentrations (1-2 x IC80). In contrast, bizelesin induced significant apoptosis only at 100 x IC80. Apoptosis induced by oxaliplatin and HMAF is sensitive to a broad spectrum caspase inhibitor Z-VAD-fmk. The "extreme case" scenarios suggest that protein damage alone may be sufficient and DNA damage per se insufficient for substantial apoptosis. Thus, for drugs which react with both DNA and protein, protein damage is worth onsidering as a factor contributing to apoptosis.
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