1. WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells.
- Author
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Wosikowski K, Mattern K, Schemainda I, Hasmann M, Rattel B, and Löser R
- Subjects
- Antineoplastic Agents antagonists & inhibitors, Apoptosis physiology, Bongkrekic Acid pharmacology, Caspase 3, Caspase 9, Caspase Inhibitors, Caspases metabolism, Cell Cycle drug effects, Cell Cycle physiology, Cytochrome c Group metabolism, DNA, Neoplasm metabolism, Enzyme Activation, Enzyme Inhibitors pharmacology, Humans, Intracellular Membranes drug effects, Intracellular Membranes physiology, Leukemia, Monocytic, Acute drug therapy, Membrane Potentials drug effects, Mitochondria drug effects, Mitochondria physiology, Poly(ADP-ribose) Polymerases metabolism, Subcellular Fractions metabolism, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Leukemia, Monocytic, Acute metabolism, Leukemia, Monocytic, Acute pathology, NAD metabolism, Organic Chemicals
- Abstract
We recently developed a class of novel antitumor agents that elicit a potent growth-inhibitory response in many tumor cells cultured in vitro. WK175, a member of this class, was chosen as a model compound that showed strong in vitro efficacy. WK175 interferes with the intracellular steady-state level of NAD(+), resulting in a decreased cellular NAD(+) concentration. We found that WK175 induces apoptotic cell death without any DNA-damaging effect. The apoptotic death signaling pathway initiated by WK175 was examined in detail: mitochondrial membrane potential, cytochrome c release, caspase 3 activation, caspase 3 and poly(ADP-ribose) polymerase cleavage, and the appearance of a sub-G(1) cell cycle population were determined in time course studies in THP-1 (a human monocytic leukemia cell line) cells. We found activation of this cascade after 24 h of treatment with 10 nM WK175. Induction of apoptosis was prevented by bongkrekic acid, Z-Asp-Glu-Val-Asp-fluoromethylketone, and Z-Leu-Glu-His-Asp-fluoromethylketone, inhibitors of the mitochondrial permeability transition and of caspase 3 and 9, respectively, but not by Ac-Tyr-Val-Ala-Asp-CHO, a specific caspase 1 inhibitor, suggesting the involvement of the permeability transition pore, caspase 3, and caspase 9 in the WK175-induced apoptotic cascade. These results imply that decreased NAD(+) concentration initiates the apoptotic cascade, resulting in the antitumor effect of WK175.
- Published
- 2002