Honokiol induces cell cycle arrest and apoptosis via inhibition of survival signals in adult T-cell leukemia

Background: Honokiol, a naturally occurring biphenyl, possesses anti-neoplastic properties. We investigated activities of honokiol against adult T-cell leukemia (ATL) associated with human T-cell leukemia virus type 1 (HTLV-1). Methods: Cell viability was assessed using colorimetric assay. Propidium iodide staining was performed to deterrnine cell cycle phase. Apoptotic effects were evaluated by 7A6 detection and caspases activity. Expressions of cell cycle- and apoptosis-associated proteins were analyzed by Western blot. We investigated the efficacy of honokiol in mice harboring tumors of HTLV-1-infected T-cell origin. Results: Honokiol exhibited cytotoxic activity against HTLV-1-infected T-cell lines and ATL cells. We identified two different effects of honokiol on HTLV-1-infected T-cell lines: cell cycle inhibition and induction of apoptosis. Honokiol induced G(1) cell cycle arrest by reducing the expression of cyclins D1, D2, E, CDK2, CDK4, CDK6 and c-Myc, while apoptosis was induced via reduced expression of clAP-2, XIAP and survivin. The induced apoptosis was also associated with activation of caspases-3 and -9. In addition, honokiol suppressed the phosphorylation of I kappa B alpha, IKK alpha, IKK beta, STAT3, STAT5 and Akt, down-regulated JunB and JunD, and inhibited DNA binding of NF-kappa B, AP-1, STAT3 and STAT5. These effects resulted in the inactivation of survival signals including NF-kappa B, AP-1, STATs and Akt. Honokiol was highly effective against ATL in mice Conclusions: Our data suggested that honokiol is a systemically available, non-toxic inhibitor of ATL cell growth that should be examined for potential clinical application. General significance: Our findings provide a rationale for clinical evaluation of honokiol for the management of ATL. (C) 2012 Elsevier B.V. All rights reserved.