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Benzylamide Sulindac Analogues Induce Changes in Cell Shape, Loss of Microtubules and G₂-M Arrest in a Chronic Lymphocytic Leukemia (CLL) Cell Line and Apoptosis in Primary CLL Cells¹

Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, Massachusetts 02118 [E-Y. M, A. L.], and the Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118 [A. L.]

Given our interest in cyclic nucleotide phosphodiesterase inhibitors in chronic lymphocytic leukemia (CLL), we studied the effects of sulindac sulfone (exisulind), a non- cyclooxygenase-inhibitory end metabolite of the NSAID sulindac that has been reported to inhibit cGMP phosphodiesterases. We focused on a novel benzylamide analogue of sulindac sulfone, CP461, which is in clinical trials as a chemotherapeutic agent. As previously reported for colon carcinoma cell lines, we found that CP461 induced a rise in cGMP levels and blocked cell proliferation in the CLL cell line WSU-CLL. Surprisingly, however, cell cycle analysis revealed that CP461 caused G₂-M arrest with an EC₅₀ of 1.1 µM. G₂-M arrest was associated with phosphorylation of Bcl2 (but not BAD, Bax, or Bcl-XL): both of these end points were abrogated by treatment with a calcium chelator. Although CP461 induces p53 up-regulation, G₂-M arrest and Bcl2 phosphorylation were independent of p53. Because microtubule-active drugs such as vincristine also induced G₂-M arrest and Bcl2 phosphorylation in WSU-CLL, whereas the genotoxic drugs etoposide and doxorubicin did not, we examined the effect of CP461 on microtubules by indirect immunofluoresence microscopy. CP461 eliminated microtubules rapidly, with reduction detected within 30 min of drug treatment. CP461 also induced marked changes in cell shape. Neither sulindac sulfide (a cyclooxygenase inhibitor) nor sulindac sulfone induced G₂-M arrest, Bcl2 phosphorylation, microtubule disassembly, or cell shape changes. Treatment with 30 µM CP461 induced greater than 50% apoptosis in 10 of 10 primary CLL leukemic cell samples, whereas the same drug concentration had only marginal effects (14% apoptosis) on whole mononuclear cells. Our work demonstrates that addition of a benzylamide moiety to sulindac compounds results in markedly altered pharmacological properties that may be of use in the therapy of lymphoid malignancies.

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