Arsenic Trioxide and the Growth of Human T-cell Leukemia Virus Type I Infected T-cell Lines

Abstract

A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As₂O₃) has been reported. Recent in vitro studies demonstrated that As₂O₃ effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As₂O₃ for the treatment of ATL is demonstrated from evidence that As₂O₃ significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As₂O₃ treated HTLV-I infected T-cell lines was induced by both apoptosis and G₁ phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As₂O₃ treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As₂O₃. Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As₂O₃ treated cells. In conclusion, As₂O₃ might become a new therapeutic tool in the treatment of ATL as As₂O₃ induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G₁ phase accumulation by enhancement of p.53, Cipl/p21, Kipl/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.

Key Words:

• adult T-cell leukemia
• arsenic trioxide
• growth inhibition
• apoptosis
• G₁ phase accumulation