Submitted April 7, 2006
Accepted September 29, 2006
Emodin and DHA potently increase arsenic trioxide interferon alpha induced cell death of HTLV-I transformed cells via generation of reactive oxygen species and inhibition of Akt and AP1
Megan Brown, Marcia Bellon, and Christophe Nicot*
University of Kansas Medical Center, United States
* Corresponding author; email: cnicot{at}kumc.edu.
Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As2O3) has been shown to effectively treat acute promyelocytic leukemia (APL) with more than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL. The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacological active dose in patients is a major obstacle since median survival of ATL patients is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon alpha (As/IFN-
) with emodin and DHA on cell cycle arrest and cell death of HTLV-I-infected cells. Importantly, we found that clinically achievable doses of DHA and Emodin allowed for reduced arsenic concentrations by 100 fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN- with emodin and DHA in ATL patients refractory to conventional therapy.
