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In acute promyelocytic leukemia (APL), the combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) appears to have a synergistic effect. Due to this synergism, differentiation syndrome (DS) in APL assumes a distinct identity separate from the formerly known ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013–2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8 %, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0–113.4) x109/L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75 %), with 68.75 % grade 3–4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced leukocyte differentiation and/or DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds. Our study, conducted in a small country with a limited number of APL patients, acknowledges the inherent constraints in sample size. Further investigations with larger patient cohorts are warranted to validate and reinforce the outcomes observed in our study. • Differentiation syndrome (DS) is known complication of APL therapy, often with challenges in diagnosis. • DS under ATRA/ATO treatment shows distinct behavior from formerly known ATRA syndrome, showing unique clinical features. • Montesinos criteria provide a framework to define DS, but they have limitations in managing senior or comorbid patients. • Leukocytosis is observed in ATO/ATRA treatment, and can be an indicator or anticipator of DS. • Hepatopathy may manifest as a ATRA/ATO-DS symptom, further studies are needed for implications for patient management. [ABSTRACT FROM AUTHOR]

To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism. The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined. The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells. ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects. • RPL22L1 is a potential biomarker for APL. • ATO inhibits aerobic glycolysis in NB4 cells. • ATO regulates glycolysis by inhibiting RPL22L1. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Arsenic trioxide-nanoliposome encapsulates were synthesized. • Stability of arsenic trioxide encapsulates with liposome was evaluated. • Stability of As(III) depends on the storing conditions. • Arsenic species were monitored by LC-ICP-MS during 90-days. Abstract In this work, we investigated the stability of arsenic trioxide (ATO) used in leukemia treatment, encapsulated with nanoliposome, with the aid of ultrasound treatment. Stability studies of As species were followed by liquid chromatography-inductively coupled plasma mass spectrometry (LC-ICP-MS), allowing for the detection of the conversion of low amounts of As(III) to As(V) or the formation of other As species. The influence of storage temperature and time on ATO was evaluated. Low amounts of As(III) to As(V) conversions were observed when the As encapsulated with nanoliposome was incubated at 25 °C and 40 °C. However, As(III) was stable if the solution was maintained at 5 °C, even after 90 days. No formation of other As species was observed, indicating good stability of the encapsulated ATO. Next step of the work will focus on spray drying of ATO nanoliposomes-encapsuleted with the aim of long term stability of As. [ABSTRACT FROM AUTHOR]

Background Acute promyelocytic leukemia (APL) is a curable form of acute myeloid leukemia; in recent years, the use of new treatment strategies, such as combination therapy, have led to improved APL outcomes. Here, outcomes of patients treated with a combination of arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are compared against patients treated with single ATO therapy. Patients and methods In total, 67 patients with non-high-risk APL were evaluated. A group of 30 patients received ATO, and another group of 37 patients received ATO plus ATRA. ATO infusion at a dose of 0.15 mg/kg/day was continued till complete remission was achieved or till 60 days of consumption, and after 28 days of rest, second ATO course was initiated for 28 days as consolidation. Four courses separated by 28-day rest were planned. In the second group, 45 mg/m 2 /day ATRA was added to ATO protocol. Results All patients except one in the ATO group and all patients in the ATO plus ATRA group were alive after a median follow-up of 18 and 17 months, respectively; 2.5-year overall survival in the ATO group was 86% ( p -value = .32). Five patients in the ATO group experienced relapse, and 2.5-year leukemia-free survival in this group was 60%. No relapse occurred in the ATO plus ATRA group ( p -value = .01). Differences in the mean of white blood cell ( p -value = .67), platelet ( p -value = .15), liver ( p -value = .37), and renal ( p -value = .95) dysfunctions were not significant. Conclusion Although ATO has been considered a first-line therapy in patients with APL, several studies have reported improved outcomes with a combination of ATO plus ATRA. This study demonstrated a significant decrease in relapse with this combination compared with single ATO therapy and supported the importance of ATRA in APL treatment. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4 mg/m 2 per day for 5–7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n = 45) or with ATO (n = 38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4 days, 10 days and 28 days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0–24 days) and day 3 (range: 0–27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score = 4, the consumption of transfused platelets was less in the RIF group than that in the ATO group ( P = 0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels ( P = 0.028) was observed in the RIF group compared with that in the ATO group ( P = 0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients. [ABSTRACT FROM AUTHOR]

Objective We aimed to compare the kinetics of white blood cell (WBC) and explore predictive factors of leukocytosis in non-high-risk acute promyelocytic leukemia (APL), with oral arsenic plus all-trans retinoic acid (ATRA) or intravenous arsenic trioxide (ATO) plus ATRA as a first-line treatment. Methods The absolute count, doubling time and peak time of WBC were analyzed in 64 newly diagnosed non-high-risk APL patients who were treated with different induction regimens containing either oral Realgar-indigo naturalis formula (RIF) (n = 35) or ATO (n = 29). The end points were the dynamic changes of the WBC counts during induction. The time points started at day 1 and were selected over 3-day intervals for 28 days. Results Among the 64 included patients, the median initial and peak WBC counts were 1.78 × 10 9 /L (range 0.31–9.89) and 12.16 × 10 9 /L (range 1.56–80.01), respectively. The incidence of differentiation syndrome was 9.38%. The dynamic changes in leukocytosis showed a single peak wave in all the patients, and the median time to peak was 10 (range 2–26) days. A higher WBC count was observed in the RIF group than in the ATO group after 10 days of treatment (9.22 × 10 9 /L vs. 4.10 × 10 9 /L, p = 0.015). Patients with the peak WBC count > 10 × 10 9 /L had a shorter WBC doubling time compared to patients with a lower peak WBC (RIF group 4 days vs. 7 days, p = 0.001; ATO group 4.5 days vs. 23 days, p = 0.002). Univariate and multivariable analyses showed that the doubling time of WBC is an independent factor for the peak WBC count. Conclusion Different kinetics of WBC proliferation were observed during induction with oral arsenic plus ATRA and ATO plus ATRA. The doubling time of WBC is an important independent factor for predicting the peak WBC count. [ABSTRACT FROM AUTHOR]

Deregulated expression of miRNAs contributes to the development of numerous malignancies, including acute myeloid leukemia (AML). The present work focused on investigating the role of miR-1306–5p in AML pathogenesis and the possible mechanisms. The expression levels of miR-1306–5p and PHF6 were assessed in 30 healthy controls and 48 newly diagnosed AML patients. CCK-8 assay, EdU staining, quantitative real-time PCR, TUNEL assay, western blots, and flow cytometry were used to characterize the changes induced by miR-1306–5p or PHF6 overexpression or inhibition. In addition, Starbase and miRWalk databases were adopted to predict the miR-1306–5p target genes. Here we reported that upregulation of miR-1306–5p was a frequent event in both primary leukemic cells from AML patients and AML cell lines. Functional assays indicated that downregulation of miR-1306–5p leads to AML cell growth arrest, less proliferation, and elevated rates of apoptosis. Mechanistically, miR-1306–5p targets PHF6, a protein that plays a key role in gene transcription regulation. Our data further showed that PHF6 was downregulated in AML patients and cell lines, and depletion of PHF6 expression using RNA interference further enhanced the proliferation while reducing the apoptosis of those leukemic cells. Our findings show that miR-1306–5p promotes proliferation and prevents apoptosis in AML by directly modulating PHF6 expression and consequently contributes to AML development and progression. miR-1306–5p may function as an oncogene in AML, providing a promising therapeutic target for AML patients. • miR-1306–3p plays an oncogene role in AML patients. • miR-1306–5p facilitates proliferation and reduces apoptosis. • miR-1306–3p promotes AML via directly targeting PHF6. • This research provides a rationale for a novel m-RNA based therapy to increase response in AML. [ABSTRACT FROM AUTHOR]

Prognostic factors for patients with acute promyelocytic leukemia (APL) treated in the context of arsenic trioxide (ATO)-based frontline regimes have not been established clearly. We retrospectively analyzed the clinical features, immunophenotypes, Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), and outcomes of 184 consecutive newly diagnosed APL patients treated by intravenous ATO-based therapy. The median age was 40 years (14–77 years). The early death rate was 4.9% (9/184 patients). With a median follow-up time of 36 months (9–74 months), the 3-year relapse-free survival (RFS) and overall survival (OS) were 93.3% and 92.2%, respectively. Interestingly, there was no meaningful association between 3-year RFS and initial white blood cell count, FLT3-ITD status, or type of PML–RARA isoforms. In multivariable analysis, the CD56 expression was the only independent risk factor in terms of RFS (hazard ratio, 4.70; P = 0.005). These results suggested that ATO-based therapy may ameliorate the unfavorable influence of previously known high-risk features; moreover, CD56 expression remains to be a potentially unfavorable prognostic factor in APL patients. [ABSTRACT FROM AUTHOR]

The incidence of acute myeloid leukemia (AML) is rising and the outcome of current therapy, which has not changed significantly in the last 40 years, is suboptimal. Cellular oxidative state is a credible target to selectively eradicate AML cells, because it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among different AML cells. To this end, we tested whether a short-time treatment of AML cells, including cells with FLT3-ITD mutation, with sub-lethal dose of dichloroacetate (DCA) (priming) followed by pharmacologic dose of arsenic trioxide (ATO) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells. Using cellular cytotoxicity, apoptotic and metabolic assays with both established AML cell lines and primary AML cells, we found that priming with DCA significantly potentiated the cytotoxicity of ATO in AML cells in a synergistic manner. The combination decreased the mitochondrial membrane potential as well as expression of Mcl-1 and GPx in primary AML cells more than either drug alone. One patient with AML whose disease was refractory to several lines of prior treatments was treated with this combination, and tolerated it well. These data suggest that targeting cellular redox balance in leukemia may provide a therapeutic option for AML patients with relapsed/refractory disease. [ABSTRACT FROM AUTHOR]

Objective The aim of this study is to investigate the growth-inhibitory and apoptosis-inducing effect of deferoxamine (DFO) combined with arsenic trioxide (ATO) on the human HL-60 xenografts in nude mice and its mechanism. Method The highly tumorigenic leukemia cell line HL-60 cells were inoculated subcutaneously into nude mice to establish a human leukemia xenograft model. The HL-60 xenograft nude mice models were randomly divided into four groups: control (Normal saline, NS), 50 mg/kg DFO, 3 mg/kg ATO, the combined treatment (50 mg/kg DFO + 1.5 mg/kg ATO) once HL-60 cells were inoculated. Tumor sizes, growth curves, inhibitory rates, cell apoptosis, and the expression of apoptosis related markers were measured to evaluate the tumor growth. Results Xenografted tumors were observed in all nude mice since the 5th day of inoculation. The inhibitory rates of tumor weight were 2.67%, 10.69%, and 25.57% in DFO, ATO and combination therapy groups, respectively. The combination of DFO with ATO induces significantly more tumor cell apoptosis than either agent alone ( p < 0.05). The expression of NF-κBp65 and survivin proteins decreased significantly while the expression of Caspase-3 and Bax increased in the combination therapy group ( p < 0.05). Double immunofluorescence for Caspase-3 and NFκBp65 demonstrated an inverse relationship between Caspase-3-positive areas and NFκBp65-positive areas, as well as the co-localization of Bax and survivin in xenografted tumor cells. Conclusions Combination of DFO and ATO has synergistic effects on tumor growth inhibition and apoptosis-inducing in vivo with no significant side effects. The DFO and ATO can up-regulate the expression of Caspase-3 and Bax, and down-regulate the expression of NF-κBp65 and survivin, especially for their combination. [ABSTRACT FROM AUTHOR]

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene. Treatment of NB4 cells with 1 μM of ATRA, 0.5 μM of ATO, or 10 μM of PP2 for 72 h induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significantly higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed with NBT staining. These effects were not related to apoptosis. Annexin-V-fluorescein staining revealed that a combination of ATRA and ATO and combination of the three agents did not induce apoptosis in NB4 cells. The expression of ICAM-1 markedly increased in cells treated with the combination of the three agents. These findings suggest that the SFK inhibitor can enhance differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL with a combination of ATRA and ATO. [ABSTRACT FROM AUTHOR]

Abstract: Arsenic trioxide (As2O3) can induce apoptosis in many tumors. However, the associated mechanisms are not clearly understood. We found that As2O3 significantly inhibited the proliferation of WSU-CLL cells and induced apoptosis in dose- and time-dependent manners. WSU-CLL cells treated with 2μM As2O3 showed survivin down-regulation and p53 up-regulation. Survivin siRNA combined with As2O3 further inhibited the proliferation of WSU-CLL cells. p53 inhibition by siRNA prevented the down-regulation of survivin by As2O3 and prevented the As2O3-induced cytotoxicity of WSU-CLL cells. These results suggest that As2O3 may be of therapeutic value for chronic lymphocytic leukemia. [Copyright &y& Elsevier]

Abstract: Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and −7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P =0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis. [Copyright &y& Elsevier]

Abstract: We conducted a retrospective study to evaluate the efficacy of combining arsenic trioxide (ATO) with all-trans-retinoic acid (ATRA) based induction therapy, followed by 3 courses of consolidation chemotherapy and 2-year sequential ATO/ATRA maintenance therapy in acute promyelocytic leukemia (APL). 137 patients were enrolled in the study. The complete remission (CR) rate was 93.4%. All the 9 (6.6%) induction failures were due to early death. With a median follow-up of 35months, 5 relapses (4%) in CR patients were recorded, including 3 isolated CNS relapses. By using the Kaplan–Meier analysis, the 5-year overall survival and relapse-free survival of the low/intermediate risk group and high-risk group was 98.9% versus 97.4% and 98.7% versus 87.9%, respectively. The results indicated that ATO based first-line protocol is highly effective for treatment of newly diagnosed APL. [Copyright &y& Elsevier]

Abstract: This study characterized the role of endoplasmic reticulum stress (ERS)-related pathways in arsenic trioxide-induced apoptosis in multidrug-resistant leukemia K562/ADM cells. Arsenic trioxide exposure led to much significant induction of apoptosis in K562/ADM cells than the parental K562 cells, and the chaperone proteins glucose-regulated protein 78, CHOP/GADD153, X-box binding protein-1 and caspase-12 were activated to varying degrees. Furthermore, arsenic trioxide stimulation led to inhibition of P-glycoprotein and Bcl-2 expression. This study demonstrates a missing link between arsenic trioxide and ERS-induced apoptosis, and suggests that the greater effects obtained in drug-resistant K562/ADM cells may be mediated by downregulation of P-glycoprotein and Bcl-2 expression. [Copyright &y& Elsevier]

Abstract: To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate±6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p =0.393) and the low-risk and high-risk group (p =0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors. [Copyright &y& Elsevier]

Abstract: Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p <0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p <0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p <0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p <0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS. [Copyright &y& Elsevier]

Abstract: Activation-induced deaminase (AID), a cytidine deaminase, can accelerate the acquisition of BCR-ABL1 kinase domain mutations in human CML. In the present study, we investigated the expression of AID and Bcr-Abl in CML cells derived from 35 clinical patients. We found that both AID and Bcr-Abl were correlatively over-expressed in CML-LBC (lymphoid blast crisis) cells as compared with those in CML-CP (chronic phase) cells. AID expression was significantly decreased in CML-LBC cells after treated with arsenic trioxide, especially together with imatinib. We also observed satisfied therapy effects of As2O3 and imatinib on patients with CML blast crisis. These data suggest that decreasing AID expression in CML-LBC by As2O3 may be a promising approach to CML treatment. [Copyright &y& Elsevier]

Abstract: Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00–1.17, P =0.04), shortened the time to achieve CR (WMD: −6.51, 95% CI: −11.32 to −1.70, P =0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14–2.66, P =0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00–1.50, P =0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO. [Copyright &y& Elsevier]

Abstract: Bleeding in acute promyelocytic leukemia (APL) is mainly associated with disseminated intravascular coagulation and hyperfibrinolysis. Annexin II (Ann II) is a co-receptor for plasminogen and tissue plasminogen activator (tPA). This study demonstrates that abnormally high levels of Ann II expression in APL cells increase the production of plasmin. Hyperfibrinolysis could be corrected by all-trans retinoic acid (ATRA) or ATRA plus arsenic trioxide therapy in patients with APL. SiRNA targetting Ann II caused a decrease in tPA-dependent plasmin generation, while Ann II cDNA transfectant stimulated plasmin production. These results suggest that Ann II play an important role in hyperfibrinolysis in APL. [Copyright &y& Elsevier]

Abstract: Advanced myelodysplastic syndrome (MDS) carries a poor prognosis. In this phase I/II study, arsenic trioxide was combined with low-dose cytarabine in 49 previously untreated patients with intermediate-2 and high-risk MDS. Complete remission was achieved in 8 (17%) patients, including 3/14 (21%) with treatment-related disease, 4/31 (13%) with unfavorable cytogenetics and 2/36 (6%) with baseline poor performance status. Mortality within the first 4 weeks was 8%. The regimen was active and had a tolerable extramedullary toxicity profile, but it was cumbersome and intensive compared to other currently available treatments. [Copyright &y& Elsevier]

Abstract: Gefitinib (Iressa, ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits growth, invasion and colony formation of various cancer cells. However, little is known about the effect of combination of gefitinib and arsenic trioxide (ATO) on differentiation of acute promyelocytic leukemia (APL). Therefore, we investigated whether gefitinib had any role in the ATO-induced differentiation of NB4 cells (APL cell line). Gefitinib induced the expression of differentiation markers including CD11b and CD14 in ATO-treated NB4 cells and facilitated ATO-induced morphologic changes and ROS generation. The results were evident that the combination of gefitinib and ATO could induce more effectively the functional differentiation of leukemic cells to macrophage-like cells. Moreover, the ERK pathway was necessary for the enhancement of gefitinib in ATO-induced differentiation, measured by CD11b and CD14 expression on NB4 cells. Therefore, our data indicated that gefitinib can play a potential role as an adjunctive differentiation agent in APL. [ABSTRACT FROM AUTHOR]

Abstract: The compromised antioxidant defense system in chronic lymphocytic leukemia (CLL) suggested a potential use for reactive oxygen species (ROS) generating arsenic trioxide (ATO) and ascorbic acid. While both ATO and ascorbic acid mediate cytotoxicity in CLL B cells as single agents, the efficacy of ATO is enhanced by ascorbic acid. This effect is dependent on increased ROS accumulation, as pretreatment of B-CLL cells with a glutathione reducing buthionine sulfoximine or catalase inhibiting aminotriazole, enhanced ATO/ascorbic acid-mediated cytotoxicity. Pretreatment with reducing agents such as catalase, or thiol antioxidant, N-acetyl cysteine or GSH also abrogated ATO/ascorbic acid-mediated cytotoxicity. Furthermore, Hu1D10-mediated cell death was enhanced with ATO and ascorbic acid, thus justifying potential combination of ATO/arsenic trioxide therapy with antibodies such as Hu1D10 that also cause accumulation of ROS. [Copyright &y& Elsevier]

Although clearly effective in acute promyelocytic leukemia (APL), arsenic trioxide (ATO) demonstrates little clinical benefit as a single agent in the treatment of non-APL hematological malignancies. We screened a library of 2000 marketed drugs and naturally occurring compounds to identify agents that potentiate the cytotoxic effects of ATO in leukemic cells. Here, we report the identification of three isothiocyanates (sulforaphane, erysolin and erucin) found in cruciferous vegetables as enhancers of ATO cytotoxicity. Both erysolin and sulforaphane significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of leukemic cell lines; erucin activity was variable among cell types. Cellular exposure to sulforaphane in combination with ATO resulted in a dramatic increase in levels of reactive oxygen species (ROS) compared to treatment with either agent alone. Sulforaphane, alone or with ATO, decreased intracellular glutathione (GSH) content. Furthermore, addition of the free radical scavenger N-acetyl-l-cysteine (NAC) rescued cells from ATO/isothiocyanate-mediated cytotoxicity. Our data suggest that isothiocyanates enhance the cytotoxic effects of ATO through a ROS-dependent mechanism. Combinatorial treatment with isothiocyanates and ATO might provide a promising therapeutic approach for a variety of myeloid malignancies. [Copyright &y& Elsevier]

Abstract: We analyzed the effect of (+)α-tocopheryl succinate (α-TOS) alone or associated with arsenic trioxide (ATO) or all-trans retinoid acid (ATRA) in acute promyelocytic leukemia (APL). α-TOS-induced apoptosis in APL clinical samples and in ATRA-sensitive (NB4) and ATRA-resistant (NB4-R2) APL cell lines. The effective dose 50% (ED-50) was calculated to be 71 and 58μM, for NB4 and NB4-R2, respectively. α-TOS neither induced nor modified ATRA-induced differentiation of APL cells, and did not affect the proliferation and differentiation of normal CD34+ hematopoietic progenitors in methylcellulose assays. α-TOS exerted a moderate antagonistic effect to ATO-induced apoptosis when treatment was done simultaneously but when α-TOS was added 24h after ATO, an additive effect was observed. Our results support the concept of α-TOS as an anti-leukemic compound which spares normal hematopoiesis. [Copyright &y& Elsevier]

Abstract: β-Catenin, the key protein in canonical Wingless/int (Wnt) pathway, degrades via ubiquitin-proteasome pathway. Recently, it proved important roles in the proliferation of myeloma cells. But little is known about whether cytoplasmic β-catenin content is associated with myeloma cell''s sensitivity to Bortezomib. We examined the constitutive expression of β-catenin in five myeloma cell lines and primary cells from patients. Meanwhile, the effect of Bortezomib combined with arsenic trioxide (As2O3)/2-methoxyestradiol (2ME2) on β-catenin accumulation, myeloma cells’ survival, apoptosis and their sensitivity to Bortezomib were also investigated. Our study proved that β-catenin protein levels are negatively associated with myeloma cells’ sensitivity to Bortezomib. As2O3/2ME2 can reduce cytoplasmic β-catenin accumulation after proteasome inhibition and enhance myeloma cells’ sensitivity to Bortezomib. This will preliminarily help to optimize the new therapeutic regimens for MM treatment in the future. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the clinical efficacy and safety of arsenic trioxide, retinoic acid and thalidomide combination therapy in higher risk MDS. Methods: Twenty-one patients diagnosed with higher risk MDS were administered 10mg/day arsenic trioxide intravenously for 10 days, 40mg/day retinoic acid orally for 2 weeks and 100mg/day thalidomide orally for 4 weeks per cycle. Results: After at least two treatment cycles, 10 patients showed hematologic responses. One achieved CR, one achieved PR, three patients achieved major hematological improvements. The efficacy rate was 24% (5/21), and the response rate was 48% (10/21). The schedule was tolerated well by all patients and toxicities were moderate and reversible. Conclusion: The combination of arsenic trioxide, retinoic acid and thalidomide could have therapeutic benefit in higher risk MDS with safety. [Copyright &y& Elsevier]

Abstract: Although recent data shows that arsenic trioxide (As2O3) is capable of inducing cell death via cell cycle arrest and apoptosis both in acute promyelocytic leukemia (APL) and in non-APL cells, the mechanisms of As2O3-mediated cell death are not fully understood. In this study, we investigated the in vitro effects of As2O3 on cell growth inhibition and cell death in human T-lymphocytic leukemia and myelodysplastic syndrome (MDS) cell lines. As2O3 significantly inhibited the proliferation of Molt-4 and Mutz-1 cells in dose- and time-dependent manner. Autophagic cell death (programmed cell death type II) and apoptosis (programmed cell death type I) were activated together in leukemia cell lines after exposed to As2O3. Numerous large cytoplasmic inclusions and vacuoles were observed in As2O3-treated cells using electron microscope. Furthermore, 3-methyladenine (an autophagy inhibitor) significantly reduced autophagic cell death and sequentially induced apoptosis. Finally, leukemia cells treated with 4μM As2O3 showed a considerable up-regulation of Beclin-1 (a Bcl-2-interacting protein) expression, which was independent of transcription of mRNA and required protein synthesis. In addition, Molt-4 cells treated with As2O3 exhibited the down-regulation of Bax protein expression, suggesting that Bax may be involved in accumulating of Beclin-1 and triggering autophagic cell death in As2O3-treated leukemia cells. These results may lead to a better understanding of the mechanism of action of As2O3, and provide a suggestion that As2O3 may be of therapeutic value for the treatment of patients with human T-lymphocytic leukemia and myelodysplastic syndrome. [Copyright &y& Elsevier]

Abstract: Arsenic trioxide (As2O3) is highly efficacious for acute promyelocytic leukemia (APL). Environmental arsenic exposure predisposes to malignancies, but the risk for therapeutic arsenic is undefined. Three APL patients (de novo, 2; therapy-related, 1) in a cohort of 59 cases given oral-As2O3 for induction and maintenance treatment developed secondary cancers (nasopharyngeal carcinoma, 2; colonic adenocarcinoma, 1) at 16, 36 and 55 months post-As2O3 therapy. Retrospective analysis of biomarkers (Epstein Barr virus serology and quantification, carcinoembryonic antigen) showed the potential presence of cancers before or shortly after As2O3 therapy, suggesting that As2O3 had not initiated these malignancies. Compared against matched background population, there was an increased risk of second cancer (p =0.012, standard incidence ratio=6.5; 95% confidence interval=1.4–19.0). [Copyright &y& Elsevier]

Acute promyelocytic leukemia (APL) is the most curable subtype of AML yet it is not known to what extent newer therapies will succeed in the very elderly. Conventional chemotherapeutic induction regimens are usually too toxic for older patients, however, all trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may be useful therapeutic options if used judiciously. This case series describes three octogenarians with APL all treated with ATRA and achieved complete remissions. The last patient received ATO at the time of first relapse and achieved a second remission. To our knowledge, this is the first report of successful use of ATO for induction in an octogenarian with APL. [Copyright &y& Elsevier]

Arsenic trioxide (As2O3) is an effective therapy for acute promyelocytic leukemia (APL), and there has been promising activity noted in other hematologic and solid tumors. The mechanism of action of As2O3 such as differentiation and apoptosis has prompted study into combination therapy. Furthermore, the connection of the sensitivity of diseases such as APL and multiple myeloma to oxidative damage has allowed the investigation of pharmacologic modulation of the cellular redox state for potentiation of As2O3. Continued study of As2O3 as a single-agent and in combination therapy will allow identification of the safest and most effective treatment regimens for malignant disease. [Copyright &y& Elsevier]

Certain cell lines like HL 60 and K 562 are utilised as leukemic cell models for leukemogenesis research, which differentiate along the granulocytic and/or monocytic pathway when treated with certain inducer molecules. High dose methylprednisolone treatment has been shown to induce in vivo and in vitro differentiation of myeloid leukemia cells to mature granulocytes in patients with acute promyelocytic leukemia (APL) and other subtypes of acute myeloid leukemia (AML). Arsenic trioxide (As2O3) has been confirmed to have remission induction effects on APL. However, there are conflicting results on the effects with other AML subtypes. Also, it has been well established that the reversible phosphorylation of proteins is a major regulatory mechanism in the signal transduction pathways that control cell growth and differentiation. Serine/threonine protein phosphatases (PP) are major components of phosphorylation. In this study, we investigated the effect of As2O3 on HL 60 and K 562 myeloid leukemic differentiation and compared the signalling cascades of the two inducers with respect to serine/threonine PP 1 and 2A. We utilised PP1 and PP2A inhibitors okadaic acid and calyculin A. In contrast to methylprednisolone, there was no effect of phosphatase inhibitors on As2O3-induced leukemic differentiation. Incomplete leukemic differentiation occurred with lower As2O3 concentration as 10−6 M. Unlike As2O3, methylprednisolone induced complete granulocytic and/or monocytic differentiation of HL 60 and K 562 cells via upregulation of PP2A regulatory subunits. Therefore, As2O3 and methylprednisolone are promising agents that have the potential to be used together in myeloid leukemic differentiation therapy. [Copyright &y& Elsevier]

• Acute promyelocytic leukemia is highly responsive to minimally myelosuppressive therapy with all-trans retinoic acid and arsenic trioxide. • Arsenic trioxide increases the risk of herpes zoster infection. • Acyclovir prophylaxis is recommended for all patients receiving arsenic trioxide. Acute Promyelocytic Leukemia (APL) is a unique subtype of acute myeloid leukemia that is highly responsive to minimally myelosuppressive therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). We and others have observed a higher than expected incidence of herpes zoster reactivation in APL patients treated with ATO. Memorial Sloan Kettering Cancer Center (MSKCC) has been using ATO since 1997 in all relapsed APL patients, and more recently has included it in our front-line APL regimens. Here we present a retrospective analysis of the factors contributing to herpes zoster reactivation among APL patients. [ABSTRACT FROM AUTHOR]

Abstract: We assessed concentrations of arsenic trioxide (As2O3) and its metabolites in the plasma and cerebrospinal fluid in acute promyelocytic leukemia patients who achieved complete remission with intravenous As2O3. Arsenic trioxide exists as high molecular mass proteins and low molecular mass proteins in the plasma, and metabolites seem to be able to penetrate blood–brain barrier. Methylarsonic acid (MA) in the cerebrospinal fluid is stably detected and its level was higher than that in plasma after As2O3 treatment. Trivalent arsenic (ASIII) and dimethylarsinic acid (DMA) became detectable after As2O3 infusion, though the levels of arsenic metabolites in the cerebrospinal fluid was lower than plasma levels. Results suggest that a combinatory treatment of As2O3 with other chemotherapeutics could be effective for APL patients with CNS involvement. [Copyright &y& Elsevier]

Abstract: We report on a 42-year-old patient whose relapse of acute promyelocytic leukaemia (APL) included meningeal infiltration. Since he had previously experienced ATRA syndrome, he received arsenic trioxide (ATO) plus intrathecal therapy with cytarabine, prednisone, and methotrexate. We measured the concentration of arsenic in his cerebrospinal fluid (CSF). Arsenic showed a peak CSF concentration of 0.008mg/l (0.11μmol/l) and a nadir of 0.002mg/l (0.027μmol/l), both representing about 14% of blood levels. ATO thus crosses the blood–CSF-barrier when administered intravenously, but the concentration in CSF is probably not sufficient for treatment of meningeal leukemia. [Copyright &y& Elsevier]

Abstract: Although new approaches have dramatically improved, the treatment of acute promyelocytic leukemia (APL) involvement of the central nervous system (CNS) confers a bad prognosis in the disease. Here, we report a patient who was diagnosed with relapsed APL preferentially involving the CNS. Treatment with arsenic trioxide led to impressive morphological changes in CNS cellularity consistent with the induction of a differentiation syndrome. Since arsenic trioxide could be identified in the CNS, we provide evidence that the drug can cross the blood-brain barrier and can be used for treatment of extramedullary APL. [Copyright &y& Elsevier]