Arsenic Trioxide and Interferon- Synergize to Induce Cell Cycle Arrest and Apoptosis in Human T-Cell Lymphotropic Virus Type I–Transformed Cells

Abstract

Human T-cell lymphotropic virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive proliferation of mature activated T cells associated with a poor prognosis. The combination of the antiviral agents, zidovudine (AZT) and  interferon (IFN), is a potent treatment of ATL. Recently, arsenic trioxide (As) was shown to be an effective treatment of acute promyelocytic leukemia (APL). We have tested the effects of the combination of As and IFN on cell proliferation, cell cycle phases distribution, and apoptosis in ATL-derived or control T-cell lines. A high synergistic effect between IFN and As was observed in ATL-derived cell lines in comparison to the control cell lines, with a dramatic inhibition of cell proliferation, G1 arrest, and induction of apoptosis. Similar results were obtained with fresh leukemia cells derived from an ATL patient. Although the mechanisms involved are unclear, these results could provide a rational basis for combined As and IFN treatments in ATL.

Treatment of adult T‐cell leukemia/lymphoma: past, present, and future

“…One French and one Japanese study that has examined the therapeutic effectiveness of arsenic trioxide with or without interferon-a in patients with relapsed ⁄ refractory ATLL found one CR and three PR in seven patients, and two PR in four patients, respectively (110,111). In addition, the Japanese study found no response in two patients administered with arsenic trioxide alone and two PR in two patients given a combination of arsenic trioxide and interferon-a, which is in accordance with the in vitro data and with the results of the French clinical study (49,110). The Japanese study also suggested that patients with moderately aggressive relapsed ⁄ refractory ATLL are promising candidates for this treatment, whereas those who are under intensive treatment or who have very aggressive ATLL do not appear to benefit from this regimen (111).…”

How animal models of leukaemias have already benefited patients

“…The latter only, actually predicts disease eradication and long-term survival. For example, the combination of arsenic and interferon alpha appears to be selectively toxic for HTLVI-infected cells that express the viral transactivator Tax (Bazarbachi et al, 1999;El-Sabban et al, 2000). This interferon/arsenic combination cures mice transplanted with murine adult T cell leukaemia (ATL) cells derived from Tax transgenics (El Hajj et al, 2010).…”

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha

“…13,14 Moreover, we showed that arsenic and interferon-alpha have synergistic effects in inhibiting proliferation and inducing apoptosis of HTLV-I-transformed adult T cell leukemia (ATL) cells. 15,16 This combination degrades the viral oncoprotein Tax, and in an ATL model derived from Tax transgenic mice, induces exhaustion of LIC. 17,18 Accordingly, promising preliminary results were achieved using the combination of arsenic and interferon-alpha in ATL patients.…”