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

• Published in: Biochimica et biophysica acta Vol. 1820; no. 7; pp. 879 - 887
• Main Authors: Ishikawa, Chie, Arbiser, Jack L., Mori, Naoki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2012
• Subjects: Adult; Adult T-cell leukemia; adults; Animals; Antineoplastic Agents, Phytogenic - pharmacology; apoptosis; Apoptosis - drug effects; biphenyl; Biphenyl Compounds - pharmacology; Blotting, Western; caspases; cell cycle checkpoints; Cell Cycle Checkpoints - drug effects; cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; cell viability; colorimetry; cyclin-dependent kinase; cyclins; cytotoxicity; DNA; Electrophoretic Mobility Shift Assay; Female; gene expression regulation; Honokiol; Human T-cell leukemia virus type 1; Humans; IKappaB kinase; leukemia; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - pathology; Lignans - pharmacology; Mice; Mice, Inbred ICR; Mice, SCID; NF-kappa B - genetics; NF-kappa B - metabolism; phosphorylation; Primate T-lymphotropic virus 1; pro-apoptotic proteins; propidium; Signal Transduction - drug effects; Signaling; T-lymphocytes; transcription factor NF-kappa B; Tumor Cells, Cultured; viruses; Western blotting; Honokiol; Human T-cell leukemia virus type 1; Signaling; Adult T-cell leukemia; Cell survival
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.03.009

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). Cell viability was assessed using colorimetric assay. Propidium iodide staining was performed to determine 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. 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 G1 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 cIAP-2, XIAP and survivin. The induced apoptosis was also associated with activation of caspases-3 and -9. In addition, honokiol suppressed the phosphorylation of IκBα, IKKα, IKKβ, STAT3, STAT5 and Akt, down-regulated JunB and JunD, and inhibited DNA binding of NF-κB, AP-1, STAT3 and STAT5. These effects resulted in the inactivation of survival signals including NF-κB, AP-1, STATs and Akt. Honokiol was highly effective against ATL in mice Our data suggested that honokiol is a systemically available, non-toxic inhibitor of ATL cell growth that should be examined for potential clinical application. Our findings provide a rationale for clinical evaluation of honokiol for the management of ATL. [Display omitted] ► Honokiol had cytotoxic activity against HTLV-1-infected T-cell lines and ATL cells. ► Honokiol reduced the expression of cyclins D1, D2, E, CDKs 2, 4, 6 and c-Myc. ► Apoptosis was induced via reduced expression of cIAP-2, XIAP and survivin. ► Honokiol was effective in mice harboring tumors of HTLV-1-infected T-cell origin. ► Inhibition of survival signals including NF-κB, AP-1, STATs and Akt confers effects.