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

Joya Chandra, Jennifer S McDonald, Son Le, David Loegering, Nancy Bone, Laura M. Bruzek, Ven L. Narayanan, Alex Adjei, Neil Elliot Kay, Ayalew Tefferi, Judith E. Karp, Edward A. Sausville, Scott H Kaufmann

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4512-4519
Number of pages8
JournalBlood
Volume102
Issue number13
DOIs
StatePublished - Dec 15 2003

Fingerprint

NSC 680410
Cytotoxicity
Reactive Oxygen Species
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cells
Buthionine Sulfoximine
Phosphorylation
Lymphoid Leukemia
DNA
Peroxides
Cell Line
Acetylcysteine
DNA Breaks
Myeloid Leukemia
K562 Cells
B-Cell Chronic Lymphocytic Leukemia
Glutathione
Acute Myeloid Leukemia
DNA Damage

ASJC Scopus subject areas

  • Hematology

Cite this

Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. / Chandra, Joya; McDonald, Jennifer S; Le, Son; Loegering, David; Bone, Nancy; Bruzek, Laura M.; Narayanan, Ven L.; Adjei, Alex; Kay, Neil Elliot; Tefferi, Ayalew; Karp, Judith E.; Sausville, Edward A.; Kaufmann, Scott H.

In: Blood, Vol. 102, No. 13, 15.12.2003, p. 4512-4519.

Research output: Contribution to journalArticle

Chandra, J, McDonald, JS, Le, S, Loegering, D, Bone, N, Bruzek, LM, Narayanan, VL, Adjei, A, Kay, NE, Tefferi, A, Karp, JE, Sausville, EA & Kaufmann, SH 2003, 'Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells', Blood, vol. 102, no. 13, pp. 4512-4519. https://doi.org/10.1182/blood-2003-02-0562
Chandra, Joya ; McDonald, Jennifer S ; Le, Son ; Loegering, David ; Bone, Nancy ; Bruzek, Laura M. ; Narayanan, Ven L. ; Adjei, Alex ; Kay, Neil Elliot ; Tefferi, Ayalew ; Karp, Judith E. ; Sausville, Edward A. ; Kaufmann, Scott H. / Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. In: Blood. 2003 ; Vol. 102, No. 13. pp. 4512-4519.
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