Tag: PCI-32765

Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with anti-tumor activity especially

Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with anti-tumor activity especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). inhibited it suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also exhibited that this knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression which were enhanced by As4S4 treatments. By contrast over-expression of SET gene resulted in PP2A downregulation and PML-RARα upregulation which were abolished by As4S4 pretreatment. Since PP2A is usually a pro-apoptotic factor and PCI-32765 PMLRARα is an anti-apoptotic factor our results suggest that As4S4-induced apoptosis in NB4-R1 cells is usually through the downregulation of SET protein expression which in turn increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis. Introduction Acute promyelocytic leukemia (APL) also known as acute progranulocytic leukemia is usually a subtype of acute myelogenous leukemia (AML). APL is usually characterized by a severe risk of early hemorrhagic death caused by a combination of disseminated intravascular coagulation (DIC) and hyperfibrinolysis [1] [2]. APL is also a morphological M3 subtype of AML and is characterized cytogenetically by a reciprocal translocation between chromosomes 15 and 17 which results in the fusion gene of promyelocytic leukemia (PML) gene and retinoic acid receptor α (RAR Rabbit Polyclonal to SFRS11. α) gene [1] [3]. This fusion protein PML-RARα binds with enhanced affinity to sites around the cellular DNA and enhances conversation of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC) thus blocking transcription differentiation of granulocytes and inhibition of apoptosis [4] [5]. All retinoic acid (ATRA) in combination with anthracycline-based chemotherapy is the standard treatment modality for APL and is able to induce total remission (CR) in most of the patients with APL through differentiation of APL blasts resulting in cure rates exceeding 80% [6] [7]. More recently arsenic trioxide (As2O3 or ATO) with or without ATRA has shown high efficacy and reduced hematologic toxicity in APL treatment and has been approved for the treatment of relapsed patients both in the United PCI-32765 States and Europe [8]. Approximately 75% patients with APL achieved CR after receiving traditional chemotherapy which includes daunorubicin (DNR) or 4-(9-acridinylamino) methanesulfan-m-anisidide (AMSA) in combination with arabinosylcytosine (Ara-C) and 6-thioguanine (TG) [9] however traditional chemotherapy can lead to early hemorrhagic death due to abnormalities of blood coagulation that occurs in most of the PCI-32765 patients at diagnosis. Although ATRA is considered to be a relatively safe drug and more than 90% APL patients were reported to achieve CR [10] [11] drug resistances and side effects such as retinoic acid syndrome and psedudotumor cerebri can occur when using ATRA (PC) [12] [13]. Therefore development of new drugs with higher efficacy and lower toxicity is still needed for APL treatment. Despite the well known toxicity of arsenic As2O3 is an efficacious agent PCI-32765 for the treatment of APL in either main or relapsed patients [14] [15] [16]. Tetra-arsenic tetra-sulfide (As4S4) is usually another arsenic compound with anti-tumor activity especially on hematological malignancies. Moreover multi-dose oral As4S4 is usually safe and relatively well tolerated in APL patients [17]. Lu et al observed that oral As4S4 was highly effective and safe in both remission induction and maintenance therapy in 129 patients with APL regardless of disease stages [18]. In addition As4S4 also has potential clinical applications when combined with imatinib in the treatment of chronic myelogenous leukemia (CML) [19]. The molecular mechanisms for the anti-tumor action of As4S4 were shown to be through the induction of apoptosis [19] PCI-32765 [20] and/or through the redistribution of PML-RARα protein in leukemic cells from APL patients [21]. Our previous study exhibited the induction ability of cellular apoptosis of As4S4 in RA-resistant cells by using a serial assays [22]. Moreover we identified several As4S4 targeted proteins such as SET/template-activating factor (TAF-1β) RPP2 and PHB by using the high-resolution two-dimensional electrophoresis system and mass spectrometry [22]. In the current study we further.