WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells
| Autor: | Katja, Wosikowski, Karin, Mattern, Isabel, Schemainda, Max, Hasmann, Benno, Rattel, Roland, Löser |
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| Rok vydání: | 2002 |
| Předmět: |
Caspase 3
Cell Cycle Antineoplastic Agents Apoptosis Cytochrome c Group DNA Neoplasm Intracellular Membranes NAD Caspase Inhibitors Caspase 9 Membrane Potentials Mitochondria Enzyme Activation Caspases Leukemia Monocytic Acute Tumor Cells Cultured Humans Enzyme Inhibitors Organic Chemicals Poly(ADP-ribose) Polymerases Bongkrekic Acid Subcellular Fractions |
| Zdroj: | Cancer research. 62(4) |
| ISSN: | 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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