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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2099-2106.
Prepublished online as a Blood First Edition Paper on September 23, 2004; DOI 10.1182/blood-2004-06-2205.
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NEOPLASIA
Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine
Tait D. Shanafelt,
Yean K. Lee,
Nancy D. Bone,
Ann K. Strege,
Ven L. Narayanan,
Edward A. Sausville,
Susan M. Geyer,
Scott H. Kaufmann, and
Neil E. Kay
From the Department of Medicine, Division of Hematology, Division of Oncology Research, and Division of Biostatistics, Mayo Clinic, Rochester, MN; Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; and Greenebaum Cancer Center, University of Maryland, Baltimore.
B-cell chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. We evaluated the ability of the investigational antileukemic agent adaphostin to induce apoptosis in CLL B cells and synergize with fludarabine in vitro. Analysis by annexin V/propidium iodide (PI) staining revealed that the concentration of adaphostin required to induce 50% cell death (IC50) at 24 hours was 4.2 µM (range, 1.10-11.25 µM; median, 4.25 µM; n = 29) for CLL isolates and more than 10 µM for B and T cells from healthy donors. Immunoblots demonstrated adaphostin induced poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage and cleavage of caspase-3 substrates, suggesting that adaphostin induces apoptosis. Adaphostin increased the level of reactive oxygen species (ROS) within CLL B cells, and the antioxidant N-acetylcysteine blocked both adaphostin-induced ROS generation and apoptosis. Adaphostin also caused a decrease in the level of the antiapoptotic protein Bcl-2. When adaphostin was combined with fludarabine (F-ARA-AMP), a synergistic effect on cell death was observed in all 10 CLL samples. These findings not only indicate that adaphostin induces apoptosis selectively in CLL B cells through a mechanism that involves ROS generation but also demonstrate its ability to augment the effects of fludarabine. Further preclinical development of adaphostin as a novel agent for the treatment of CLL appears warranted.
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