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Blood, 15 July 2005, Vol. 106, No. 2, pp. 690-697.
Prepublished online as a Blood First Edition Paper on March 31, 2005; DOI 10.1182/blood-2004-11-4273.
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Submitted November 12, 2004
Accepted March 25, 2005
The natural product Honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells
Traci E Battle, Jack Arbiser, and David A Frank*
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
* Corresponding author; email: david_frank{at}dfci.harvard.edu.
B-CLL remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Honokiol is a natural product known to possess potent anti-neoplastic and anti-angiogenic properties. We examined whether honokiol can overcome apoptotic resistance in primary tumor cells derived from B-CLL patients. Honokiol induced caspase-dependent cell death in all of the B-CLL cells examined and was more toxic toward B-CLL cells than to normal mononuclear cells, suggesting greater susceptibility of the malignant cells. Honokiol-induced apoptosis was characterized by the activation of caspases 3, 8, and 9 and cleavage of PARP. Exposure of B-CLL cells to honokiol resulted in up-regulation of bax and down-regulation of the expression of the key survival protein Mcl-1, which is associated with response to treatment in B-CLL patients. In addition, B-CLL cells pre-treated with IL-4, a cytokine known to support B-CLL survival, underwent apoptosis when subsequently incubated with honokiol, indicating that honokiol could also overcome the pro-survival effects of IL-4. Furthermore, honokiol enhanced cytotoxicity induced by fludarabine, cladribine, or chlorambucil. These data indicate that honokiol is a potent inducer of apoptosis in B-CLL cells and should be examined for further clinical application either as a single agent or in combination with other anticancer agents.
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