Acute promyelocytic leukemia drug - arsenic trioxide in the presence of eugenol shows differential action on leukemia cells (HL-60) and cardiomyocytes (H9c2) - inference from NMR study.

The increased concern of cardiovascular dysfunction by cancer therapeutics has led to more effective treatment strategies. Arsenic trioxide (As2O3) is a potential chemotherapeutic agent for acute promyelocytic leukemia (APL), but the effectiveness is affected by potential cardiotoxicity. Researchers have been trying to find out novel modalities to manage the adverse effects of As2O3. In our study, the antioxidant molecule eugenol showed protective action against the destructive impact of As2O3 on cardiomyocytes (H9c2) without compromising the anti-cancer property As2O3 on leukemia cells (HL-60). We have studied the interaction between arsenic and eugenol in physiological and acidic pH to understand the molecular mechanism of differential action of As2O3 in the presence of eugenol using NMR spectroscopy. The study observed that at physiological pH, arsenic and eugenol interact to form an inactive product, positively affecting H9c2 cardiomyocytes. Still, there is no such interaction in acidic pH evidenced by the useful anti-cancer property of As2O3. The result concludes that the antioxidant molecule eugenol is an efficient protective agent against the adverse effect of As2O3 on cardiomyocytes.

Protective Effects of Eugenol against Hepatotoxicity Induced by Arsenic Trioxide: An Antileukemic Drug.

BACKGROUND: Arsenic trioxide (As2O3) has shown effectiveness in the treatment of leukemia, but it is also associated with hepatotoxicity. Given antileukemic drug-induced oxidative stress and toxicity, this study focused on the mitigatory role of eugenol, a monoterpene compound from clove oil, in the hepatic tissue of Wistar rats. METHODS: Twenty-four male Wistar rats (180-250 g) were randomly divided into 4 groups (6 rats per group): normal control rats, rats treated with As2O2 (4 mg/kg bwt), rats treated with eugenol (5 mg/kg bwt), and rats receiving co-treatment with As2O3 (4 mg/kg bwt) and eugenol (5 mg/kg bwt), all of which orally administered for a period of 30 days. The Tukey test (Origin version 7, Origin Lab Corporation, Northampton, USA) was applied to analyze the one-way analysis of variance (ANOVA) between the different groups. A P value less than 0.05 was considered significant. RESULT: Oral administration of As2O3 significantly induced hepatic damage, evident from increased levels of aspartate transaminase and alanine transaminase (P=0.01 and P<0.001, respectively). Moreover, a decrease in the activities of enzymatic and nonenzymatic antioxidants altered electrolyte concentration and increased the rate of lipid peroxidation (P=0.04) and the level of nitric oxide (P=0.01). Accumulation studies and histopathological analyses confirmed the biochemical variations. Co-treatment with eugenol (5 mg/kg bwt) exhibited hepatoprotective effects as manifested by the decreased rate of arsenic accumulation, lipid peroxidation, and nitric oxide level along with normalized levels of antioxidants and maintained histology of the liver. CONCLUSION: Eugenol may be used in combination with arsenic trioxide in chemotherapy to reduce oxidative damage to the hepatic system.

L-Ascorbic Acid and α-Tocopherol Reduces Hepatotoxicity Associated with Arsenic Trioxide Chemotherapy by Modulating Nrf2 and Bcl2 Transcription Factors in Chang liver Cells.

Arsenic trioxide (As2O3) is a promising new regimen for the treatment of acute promyelocytic leukemia (APL). The induction of oxidative stress mediated by reactive oxygen species (ROS) and excessive intracellular calcium influx are the main reasons behind As2O3 toxicity. Since liver is the major organ for xenobiotic metabolism, it is always under stress. Antioxidant vitamins such as L-Ascorbic acid (L-AA) and α-Tocopherol (α-TOC) have been proposed to have beneficial effects against a variety of pathological conditions and are known by their free radical scavenging properties. The present study evaluates the curative efficacy of L-AA and α-TOC against As2O3 toxicity using immortalized human Chang liver cells. Our results suggest that L-AA (100 µM) and α-TOC (50 µM) recovered As2O3 (10 µM) cytotoxicity. Furthermore, As2O3 treatment showed an increase in lipid peroxidation and depletion in antioxidant status, mitochondrial trans membrane potential and values of total antioxidant capacity. Cotreatment of antioxidant vitamins with As2O3 resulted in a significant reversal of oxidative stress markers. Our findings substantiate the effect of antioxidant vitamins in protecting the hepatocytes from oxidative stress which may be attributed through Nrf2 (Nuclear factor erythroid 2-related factor 2) mediated upregulation of Bcl2 (B-cell lymphoma 2) expression.

L-ascorbic acid and α-tocopherol attenuate arsenic trioxide-induced toxicity in H9c2 cardiomyocytes by the activation of Nrf2 and Bcl2 transcription factors.

Arsenic trioxide (As2O3) is a potent drug for the treatment of acute promyelocytic leukemia (APL) and has achieved remarkable remissions in patients. Unfortunately, clinical reports have shown that the treatment is associated with cardiotoxicity. Many efforts have been made to mitigate drug-mediated cardiac damage using naturally occurring antioxidant compounds possessing free radical scavenging activity. The present investigation aims to explore protective role of L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) from As2O3-induced oxidative stress in H9c2 cardiomyocytes through the evaluation of Nrf2 (nuclear factor erythroid 2-related factor 2) and Bcl-2 (B-cell lymphoma 2) transcription factors. The in vitro study was conducted using H9c2 cardiomyocytes. The evaluation of total antioxidant capacity, mitochondrial membrane potential, cellular calcium concentration and reactive oxygen species generation was performed. Oxidative stress (Nrf2) and anti-apoptotic (Bcl2) signaling indicators were measured by reverse transcriptase polymerase chain reaction. A depletion of the total antioxidant capacity and mitochondrial transmembrane potential were observed in As2O3-treated cardiomyocytes. In addition, the cellular calcium concentration and ROS generation were found to be increased on treatment with As2O3 with the alterations in the activity of transcription factors, Nrf2 and Bcl2. Co-treatment of antioxidant vitamins with As2O3 resulted in a significant reversal of oxidative stress and alteration on the antioxidant defense through the activation of Nrf2 and Bcl2. L-AA and α-TOC alleviates As2O3-induced oxidative stress in cardiac cells by activating Nrf2 and Bcl2 transcription factors that results in increased cell survival and prevents apoptosis.

Studies on curative efficacy of monoterpene eugenol on anti- leukemic drug arsenic trioxide induced cardiotoxicity.

BACKGROUND: Arsenic trioxide (As2O3) is emerging as a frontline agent for the treatment of acute promyelocytic leukemia (APL) but the therapeutic application is limited by its toxicity. QT prolongation, torsades de pointes and sudden cardiac death have been implicated in the As2O3 therapy. So eugenol is a monoterpene compound is well known for its antioxidant properties and protective effect on the cardiovascular system. OBJECTIVE: In this study, the cardioprotective effect of eugenol on cardiac electrical conductivity, tissue electrolytes, myocardial markers, antioxidant system, lipid peroxidation and nitric oxide production was investigated in male Wistar rats treated with arsenic trioxide. RESULTS: The Inductively coupled plasma emission spectroscopic (ICP-OES) analysis pointed out the accumulation of arsenic in heart tissue. The rats administered with arsenic trioxide (4mg/kg body wt) exhibited myocardial damage that was manifested by the elevation of cardiac markers (LDH, CK-MB) enzymes and deterioration in the antioxidant enzymes (GSH, GST, GPx). Combination treatment with eugenol (5mg/kg of body wt) upholds the tissue antioxidant level, Na+/K+ - ATPase and Ca2+- ATPase activity and brings the cytosolic Ca2+, K+ and Na + levels near to normal value. Conjoined therapy with eugenol ameliorated the membrane peroxidation, restored the normal heart rate and rectified the prolongation of QT interval in the electrocardiogram. Histological examination of cardiac segments also supported the beneficial role of eugenol against arsenic-induced oxidative damages. CONCLUSION: Our in vivo experimental findings suggest that monoterpenoid eugenol could be a potent and novel cytoprotective agent of clinical application against As2O3 induced cardiotoxicity.