WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells.

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.

• Authors: Katja Wosikowski, Karin Mattern, Isabel Schemainda, Max Hasmann, Benno Rattel, Roland Löser
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 4 Pg. 1057-62 (Feb 15 2002) ISSN: 0008-5472 [Print] United States
• PMID: 11861382 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Caspase Inhibitors
• Cytochrome c Group
• DNA, Neoplasm
• Enzyme Inhibitors
• Organic Chemicals
• WK175
• NAD
• Bongkrekic Acid
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• Caspases

Topics

• Antineoplastic Agents (antagonists & inhibitors, pharmacology)
• Apoptosis (drug effects, physiology)
• Bongkrekic Acid (pharmacology)
• Caspase 3
• Caspase 9
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Cycle (drug effects, physiology)
• Cytochrome c Group (metabolism)
• DNA, Neoplasm (metabolism)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Humans
• Intracellular Membranes (drug effects, physiology)
• Leukemia, Monocytic, Acute (drug therapy, metabolism, pathology)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, physiology)
• NAD (metabolism)
• Organic Chemicals
• Poly(ADP-ribose) Polymerases (metabolism)
• Subcellular Fractions (metabolism)
• Tumor Cells, Cultured