Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in Myeloid Leukemia Cell Lines and Function in a PML and PML-RAR Independent Manner

Abstract

Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has been proposed to principally target PML and PML-RAR proteins in APL cells. We investigated the activity of As2O3 and melarsoprol in a broader context encompassing various myeloid leukemia cell lines, including the APL cell line NB4-306 (a retinoic acid–resistant cell line derived from NB4 that no longer expresses the intact PML-RAR fusion protein), HL60, KG-1, and the myelomonocytic cell line U937. To examine the role of PML in mediating arsenical activity, we also tested these agents using murine embryonic fibroblasts (MEFs) and bone marrow (BM) progenitors in which the PML gene had been inactivated by homologous recombination. Unexpectedly, we found that both compounds inhibited cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10−7 to 10−5 mol/L. As2O3 relocalized PML and PML-RAR onto nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60 and U937 cell lines. Although melarsoprol was more potent in inhibiting growth and inducing apoptosis, it did not affect PML and/or PML-RAR nuclear localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth and induced apoptosis of PML+/+ and PML−/− MEFs, and inhibited colony-forming unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of PML+/+ and PML−/− progenitors. Together, these results show that As2O3 and melarsoprol inhibit growth and induce apoptosis independent of both PML and PML-RAR expression in a variety of myeloid leukemia cell lines, and suggest that these agents may be more broadly used for treatment of leukemias other than APL. © 1998 by The American Society of Hematology.

Risk/Benefit Profile of Arsenic Trioxide

“…In Western medicine, before the development of penicillin, arsenic (the "silver bullet") was used by Ehrlich to treat syphilis [8]. It was also the active agent in Fowler's solution, which was commonly used to control the leukocytosis in patients with chronic myelocytic leukemia [9]. 30 Risk/Benefit Profile of Arsenic Trioxide These early therapeutic uses of arsenic were essentially discontinued in the 1930s as more conventional therapies became available [1].…”

“…30 Risk/Benefit Profile of Arsenic Trioxide These early therapeutic uses of arsenic were essentially discontinued in the 1930s as more conventional therapies became available [1]. Until recently, the only available medicinal arsenic-based compound approved for human use was melarsoprol, which is used to treat trypanosomiasis (African sleeping sickness) involving the central nervous system [9].…”

Dual effects of arsenic trioxide (As2O3) on non‐acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation

“…et al, 1999). Moreover, the potency of As 2 O 3 to induce apoptosis was shown for non-APL leukaemia and lymphoma cell lines (Konig et al, 1997;Wang et al, 1998;Lu et al, 1999;Zhu et al, 1999;Puccetti et al, 2000;Walter et al, 2000) as well as other tumour cell lines (Akao et al, 1999;Huang, C. et al, 1999;Zhang et al, 1999;Deng et al, 2000;Chen, F. et al, 2001;Jiang et al, 2001). The necessity of the PML-RARa fusion protein present in APL-cell lines for As 2 O 3 -induced apoptosis thus became questionable.…”

Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies

“…Anderson Cancer Center (Houston, TX), investigators are using the same dose for 15-30 days to treat patients with chronic-phase CML who are refractory to or intolerant of IFN-α. Although these doses are higher than those usually given in APL, preclinical data suggest that AML [7,8] and malignant lymphoid cells [9] may require higher levels of arsenic to inhibit growth and induce apoptosis.…”