Arsenic Trioxide and Resveratrol Show Synergistic Anti-Leukemia Activity and Neutralized Cardiotoxicity

Abstract

Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity.

LukS-PV, a component of Panton-Valentine leukocidin, exerts potent activity against acute myeloid leukemia in vitro and in vivo

“…Some studies report that anti-cancer toxins could be appropriately designed or combined with other drugs to reduce toxicity (Fan et al, 2014;Tan et al, 2012). In our study, when LukS-PV, a component of PVL, was given at the high dose of 1200 g/kg, no obvious pathological changes in organs or mice death were observed.…”

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

“…Gene manipulation research has also confirmed the effects of antioxidants, which can be applied in prevention strategies against PAH. Resveratrol (Rev, 3,5,4-trihydroxystilbene), a polyphenol isolated from grapes and polygonum cuspidatum, has been shown to possess antioxidative properties [17]. A recent study showed that Rev could reverse monocrotaline-induced pulmonary vascular remodelling and prevent the progression of PAH [18, 19].…”

Metabolomics Reveals Protection of Resveratrol in Diet-Induced Metabolic Risk Factors in Abdominal Muscle

“…Previous findings from our lab show that Rev protects against cardiomyocytes apoptosis induced by As 2 O 3 through attenuating oxidative stress [18]. In addition, we found that Rev could ameliorate cardiac hypertrophy by attenuation level of miR-155 through activation of Breast Cancer Type 1 Susceptibility Protein (BRCA1) [19].…”