title: 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.
authors.affiliation: College of Pharmacy, Harbin Medical University-Daqing, Daqing, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Respiratory Medicine, the Fourth Hospital of Harbin Medical University, Harbin, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Geriatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Meng
authors.affiliation: College of Pharmacy, Harbin Medical University-Daqing, Daqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Cardiology, the Fourth Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Radiology Department and Key Laboratory of Molecular Imaging, the Fourth Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wan
authors.affiliation: College of Pharmacy, Harbin Medical University-Daqing, Daqing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Fang
authors.affiliation: Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D010087:Oxides / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000009:adverse effects / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D001152:Arsenicals; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013482:Superoxide Dismutase; D000077185:Resveratrol; D000077237:Arsenic Trioxide