Affiliation:
1. From the Department of Medicine, Karmanos Cancer Institute, Wayne State University, and the John D Dingell VA Medical Center, Detroit, MI; the Burnham Institute, La Jolla, CA; College of Pharmacy, Oregon State University, Corvallis; and Galderma R and D, Sophia Antipolis, France.
Abstract
We have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) that induces apoptosis in a number of malignant cell types. We now describe our studies examining the effects of CD437 and a nonretinoidal analog (MM002) on the in vitro proliferation of the ALL-REH cell line, the in vitro and in vivo growth of a novel Epstein-Barr virus–negative (EBV−) B-cell chronic lymphocytic leukemia (B-CLL) cell line (WSU-CLL), and primary cultures of human B-CLL and acute lymphoblastic leukemia (ALL) cells. CD437 and MM002 induce apoptosis in both cell lines, as indicated by the activation of caspase-2 and caspase-3, cleavage of poly(adenosine diphosphate–ribose) (poly(ADP-ribose)) polymerase, increase in annexin V binding, and subsequent nuclear fragmentation. CD437-mediated apoptosis was not associated with the modulation of Bcl-2, Bax, or Mcl-1 levels, but was associated with the cleavage of the antiapoptotic protein Bcl-XL to a proapoptotic 18-kD form. This cleavage of Bcl-XL was dependent on caspase-3 activation since Bcl-XL cleavage and apoptosis were inhibited by the caspase-3 inhibitor Z-DVED-fmk. CD437 markedly inhibited the growth of WSU-CLL cells in severe combined immunodeficiency (SCID) mice. Tumor growth inhibition, growth delay, and log cell kill were 85.7%, 21 days, and 2.1, respectively, in the treated mice. Moreover, 1 of the 5 treated mice was tumor-free longer than 150 days and thus was considered cured. Exposure of primary cultures of both B-CLL and ALL cells obtained from patients to CD437 and MM002 resulted in their apoptosis. These results suggest that CD437 and MM002 analogs may have a potential role in the treatment of B-CLL and ALL.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Reference66 articles.
1. Chronic lymphocytic leukemia: new insights into biology and therapy.;Foon;Ann Int Med.,1990
2. Molecular biology of chronic lymphocytic leukemia.;Reed;Semin Oncology.,1998
3. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses.;Kitada;Blood.,1998
4. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of Bcl-2 and BAX.;McConkey;J Immunol.,1996
5. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells.;Schena;Blood.,1992
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