Arsenic trioxide and the growth of human T-Cell leukemia virus type I infected T-Cell lines

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 ri:mains 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 G(1) phase accumulation. Cleaved bcl-2 protein and an enhanced expression of I,ak 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 p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.