Sacubitril/valsartan protects against arsenic trioxide induced cardiotoxicity in vivo and in vitro.

The cardiotoxicity induced by arsenic trioxide (ATO) limits its clinical application in acute promyelocytic leukemia treatment. Sacubitril/valsartan (LCZ696) is an effective drug for the treatment of heart failure. In this study, we aimed to investigate the protective effect and mechanisms of LCZ696 against the ATO-induced cardiotoxicity in mice and H9c2 cells. We found that LCZ696 could alleviate the decrease of ejection fraction and fractional shortening induced by ATO, thereby improving mouse cardiac contractile function. LCZ696 could also reduce the myocardial enzyme, resist oxidative stress, mitigate myocardial fibrosis, and ameliorate myocardial structure, thereby alleviating myocardial damage caused by ATO. In addition, LCZ696 could significantly increase the cell viability and reduce the accumulation of reactive oxygen species in ATO-treated H9c2 cells. Besides, in vivo and in vitro studies have been found that LCZ696 could restore the expression of Bcl-2 and reduce Bax and Caspase-3 levels, inhibiting ATO-induced apoptosis. Meanwhile, LCZ696 decreased the levels of IL-1, IL-6, and TNF-α, alleviating the inflammatory injury caused by ATO. Furthermore, LCZ696 prevented NF-κB upregulation induced by ATO. Our findings revealed that LCZ696 has a considerable effect on preventing cardiotoxicity induced by ATO, which attributes to its capability to suppress oxidative stress, inflammation, and apoptosis.

Arsenic Trioxide Therapy During Pregnancy: ATO and Its Metabolites in Maternal Blood and Amniotic Fluid of Acute Promyelocytic Leukemia Patients.

Acute promyelocytic leukemia (APL) is extremely fatal if treatment is delayed. Management of APL in pregnancy is a challenging situation. Arsenic trioxide (ATO) is successfully applied to treat APL. ATO can be transformed into different arsenic species [arsenite (AsIII), monomethylated arsenic (MMA, consists of MMAIII and MMAV), dimethylated arsenic (DMA, consists of DMAIII and DMAV), and arsenate (AsV)], which produce different toxic effects. Investigating the maternal and fetal exposure to arsenic species is critical in terms of assessing maternal and fetal outcomes, choice of optimal treatment, and making decisions for attempting to preserve the obstetrical and fetal wellbeing. In this study, maternal blood and amniotic fluid (AF) from APL patients treated with ATO in pregnancy and blood samples of non-pregnant patients were collected. Concentrations of inorganic arsenic (iAs, iAs = AsIII+AsV), MMA, and DMA were analyzed by high-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The difference in arsenic species of plasma between pregnant patients and non-pregnant patients, distribution of arsenic compounds in AF and maternal plasma, and arsenic penetration into AF were explored. The outcomes of pregnant women treated with ATO and their fetus were analyzed. No significant differences in arsenic concentration, percentage, and methylation index [PMI: primary methylation index (MMA/iAs); SMI: secondary methylation index (DMA/MMA)] between pregnant women and non-pregnant women (p > 0.05) were observed. The mean ratios of AF to maternal plasma were as follows: iAs, 2.09; DMA, 1.04; MMA, 0.49; and tAs, 0.98. Abortion rate is higher with the diagnosis at an earlier gestational age, with 0%, 67%, and 100% of pregnancies ending in abortion during the third, second, and first trimester, respectively. The age of the pregnant women, the dose of ATO, and the duration of fetal exposure in utero had no influence on fetal outcomes. All APL women achieved complete remission (CR). Collectively, ATO and its metabolites can easily cross the placenta. Levels and distribution of arsenic species in maternal plasma and AF gave evidence that arsenic species had a different ability to penetrate the placenta into AF (iAs > DMA > MMA) and indicated a relatively high fetal exposure to ATO and its metabolites in utero. Gestational age at diagnosis was more likely to be closely related to fetal outcomes, but had no effects on mother outcomes.

Effect of renal impairment on arsenic accumulation, methylation capacity, and safety in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.

Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Characteristics and influence factors of arsenic species in APL patients have not been studied.Methods: 305 plasma samples from APL patients treated with ATO were analyzed using HPLC-HG-AFS. Trough concentration (Ctrough), distribution, methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and association between arsenic concentrations and clinical efficacy were explored.Results: Ctrough of arsenic in effective treatment groups provide basis for defining the target range of arsenic plasma concentrations in APL patients treated with ATO. Distribution trends: DMAV > AsIII, MMAV> AsV (p < 0.0001) for continuous slow-rate (CS) infusion and DMAV > MMAV > AsIII > AsV (p < 0.0001) for conventional infusion. Infusion methods and combined medication may affect arsenic metabolism. There was a weak correlation between ATO dose and plasma Ctrough of arsenic species. Ctrough of plasma arsenic species had predictive value for treatment efficacy.Conclusion: Arsenic concentration monitoring in APL patients treated with ATO is required. These findings are critical to optimize treatment outcomes of ATO therapy.

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol.

Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood-brain barrier (BBB) permeability for arsenic. Arsenite (AsIII ), monomethylarsonic acid (MMAV ), dimethylarsinic acid (DMAV ), and arsenate (AsV ) in CSF and plasma were analysed by high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII , DMAV > MMAV > AsV . Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV . Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.

Polymorphisms in arsenic (+ 3 oxidation state) methyltransferase (AS3MT) predict the occurrence of hyperleukocytosis and arsenic metabolism in APL patients treated with As2O3.

Polymorphisms in arsenic (+ 3 oxidation state) methyltransferase (AS3MT) have been shown to be related to interindividual variations in arsenic metabolism and to influence adverse health effects in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (As2O3). The occurrence of hyperleukocytosis with As2O3 treatment seriously affects the early survival rate of APL patients, but no definite explanation for such a complication has been clearly established. To clarify the causes of this situation, AS3MT polymorphisms 14215 (rs3740390), 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) and profiles of plasma arsenic metabolites were evaluated in a group of 54 newly diagnosed APL patients treated with single-agent As2O3. High-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) was used to determine the concentrations of plasma arsenic metabolites. Plasma arsenic methylation metabolism capacity was evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), primary methylation index (PMI, MMA/iAs), and secondary methylation index (SMI, DMA/MMA). The results showed that APL patients who developed hyperleukocytosis had a higher plasma iAs%, but a lower MMA% and PMI than those who did not develop hyperleukocytosis during As2O3 treatment. In addition, patients with the AS3MT 14215 (rs3740390) CC genotype had significantly higher plasma iAs% and incidence of hyperleukocytosis, but lower PMI than patients with the CT + TT genotype. Conversely, we did not observe statistically significant associations between the occurrence of hyperleukocytosis and AS3MT 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) polymorphisms in our study subjects. These results indicated that AS3MT 14215 (rs3740390) might be used as an indicator for predicting the occurrence of hyperleukocytosis in APL patients treated with As2O3.