Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells.
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.
Chandra
Joya
J
Division of Oncology Research, Guggenheim 1301, Mayo Clinic, 200 First St, SW, Rochester, MN 55901, USA.
Hackbarth
Jennifer
J
Le
Son
S
Loegering
David
D
Bone
Nancy
N
Bruzek
Laura M
LM
Narayanan
Ven L
VL
Adjei
Alex A
AA
Kay
Neil E
NE
Tefferi
Ayalew
A
Karp
Judith E
JE
Sausville
Edward A
EA
Kaufmann
Scott H
SH
D000111:Acetylcysteine / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000032:analysis; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007938:Leukemia / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011809:Quinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins / Q000494:pharmacology
D000975:Antioxidants; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D006873:Hydroquinones; C480582:NSC 676537; C404397:NSC 680410; D009363:Neoplasm Proteins; D011809:Quinones; D017382:Reactive Oxygen Species; D020032:Tyrphostins; C104965:tyrphostin AG957; D019328:Buthionine Sulfoximine; D016044:Fusion Proteins, bcr-abl; D005978:Glutathione; D000218:Adamantane; D000111:Acetylcysteine