Human
T-cell leukemia virus type 1 (HTLV-1) is the causative agent of
adult T-cell leukemia/lymphoma (
ATLL) but there is no effective treatment for HTLV-1-associated diseases. Herein, we determined the effect of
butein, a bioactive plant
polyphenol, on cell growth, apoptosis and signaling pathways in HTLV-1-infected T-cell lines and on
tumor growth in SCID mice. Treatment with
butein caused a decrease in viability of HTLV-1-infected T-cell lines. T cells cultured with
butein showed obvious apoptosis morphology, and cleavage of
poly(ADP-ribose) polymerase with activation of
caspase-3, -8 and -9. Pretreatment of cells with
caspase inhibitor partially blocked
butein-induced inhibition of cell viability.
Butein also resulted in cell cycle arrest at G1 phase.
Butein markedly downregulated the
protein expression levels of CDK4, CDK6,
cyclin D1,
cyclin D2,
cyclin E,
survivin, XIAP, c-IAP2 and phospho-pRb.
Butein also inhibited i) total and phospho-
protein levels of IκB
kinase (IKK)α and IKKβ, ii) degradation and phosphorylation of IκBα, iii) JunB and JunD, iv) total and phospho-
protein levels of Akt, v) phosphorylation of RelA, vi) heat
shock protein 90, and vii)
DNA-binding activity of NF-κB and AP-1. In mice harboring
ATLL xenograft
tumors,
butein caused a significant inhibition of
tumor growth and reduced serum levels of soluble
interleukin-2 receptor α chain and soluble cluster of differentiation 30. Considered together, the results indicated that
butein has antiproliferative and proapoptotic properties through the suppression of NF-κB, AP-1 and Akt signaling in HTLV-1-infected T cells, both in vitro and in vivo, suggesting its therapeutic potential against HTLV-1-associated diseases including
ATLL.