1. Potentiation of temozolomide cytotoxicity by poly(ADP)ribose polymerase inhibitor ABT-888 requires a conversion of single-stranded DNA damages to double-stranded DNA breaks.
- Author
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Liu X, Shi Y, Guan R, Donawho C, Luo Y, Palma J, Zhu GD, Johnson EF, Rodriguez LE, Ghoreishi-Haack N, Jarvis K, Hradil VP, Colon-Lopez M, Cox BF, Klinghofer V, Penning T, Rosenberg SH, Frost D, Giranda VL, and Luo Y
- Subjects
- Animals, Cell Death drug effects, Cell Line, Tumor, DNA Repair drug effects, DNA Replication drug effects, Dacarbazine pharmacology, Disease Models, Animal, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Mice, Rats, Temozolomide, Antineoplastic Agents pharmacology, Benzimidazoles pharmacology, DNA Breaks, Double-Stranded drug effects, DNA Breaks, Single-Stranded drug effects, Dacarbazine analogs & derivatives, Poly(ADP-ribose) Polymerase Inhibitors
- Abstract
Poly(ADP-ribose) polymerase (PARP) senses DNA breaks and facilitates DNA repair via the polyADP-ribosylation of various DNA binding and repair proteins. We explored the mechanism of potentiation of temozolomide cytotoxicity by the PARP inhibitor ABT-888. We showed that cells treated with temozolomide need to be exposed to ABT-888 for at least 17 to 24 hours to achieve maximal cytotoxicity. The extent of cytotoxicity correlates with the level of double-stranded DNA breaks as indicated by gammaH2AX levels. In synchronized cells, damaging DNA with temozolomide in the presence of ABT-888 during the S phase generated high levels of double-stranded breaks, presumably because the single-stranded DNA breaks resulting from the cleavage of the methylated nucleotides were converted into double-stranded breaks through DNA replication. As a result, treatment of temozolomide and ABT-888 during the S phase leads to higher levels of cytotoxicity. ABT-888 inhibits poly(ADP-ribose) formation in vivo and enhances tumor growth inhibition by temozolomide in multiple models. ABT-888 is well tolerated in animal models. ABT-888 is currently in clinical trials in combination with temozolomide.
- Published
- 2008
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