Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-I-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1.
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 greater 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 pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon alpha (As/IFN-alpha) 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-alpha with emodin and DHA in patients with ATL refractory to conventional therapy.
Brown
Megan
M
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, Kansas City 66160, USA.
Bellon
Marcia
M
Nicot
Christophe
C
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004642:Emodin / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D016898:Interferon-alpha / Q000187:drug effects*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
D001152:Arsenicals; D016898:Interferon-alpha; D010087:Oxides; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D004281:Docosahexaenoic Acids; D051057:Proto-Oncogene Proteins c-akt; D004642:Emodin; D000077237:Arsenic Trioxide