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WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells.
- Source :
-
Cancer research [Cancer Res] 2002 Feb 15; Vol. 62 (4), pp. 1057-62. - Publication Year :
- 2002
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 62
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 11861382