Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells.

Abstract

Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned.

• Authors: Joya Chandra, Jennifer Hackbarth, Son Le, David Loegering, Nancy Bone, Laura M Bruzek, Ven L Narayanan, Alex A Adjei, Neil E Kay, Ayalew Tefferi, Judith E Karp, Edward A Sausville, Scott H Kaufmann
• Journal: Blood (Blood) Vol. 102 Issue 13 Pg. 4512-9 (Dec 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12920036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• DNA, Neoplasm
• Enzyme Inhibitors
• Hydroquinones
• NSC 676537
• NSC 680410
• Neoplasm Proteins
• Quinones
• Reactive Oxygen Species
• Tyrphostins
• tyrphostin AG957
• Buthionine Sulfoximine
• Fusion Proteins, bcr-abl
• Glutathione
• Adamantane
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Adamantane (analogs & derivatives, pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Buthionine Sulfoximine (pharmacology)
• DNA Damage
• DNA, Neoplasm (drug effects)
• Enzyme Inhibitors (pharmacology)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Glutathione (analysis)
• Humans
• Hydroquinones (pharmacology)
• K562 Cells (drug effects, metabolism)
• Leukemia (pathology)
• Leukemia, Lymphocytic, Chronic, B-Cell (pathology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology)
• Leukemia, Myeloid (pathology)
• Neoplasm Proteins (antagonists & inhibitors)
• Neoplastic Stem Cells (drug effects)
• Quinones (pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Stem Cell Assay
• Tyrphostins (pharmacology)