Artemisinin Enhances The Anticancer Effects Of Arsenic Trioxide And Attenuates Its Cardiotoxicity

Arsenic trioxide (As2O3) has been demonstrated to be an effective therapeutic agent in in patients with relapsed or refractory acute promyelocytic leukemia (APL), and the CR rate in relapsing APL after treatment with As2O3 is as high as 80-90%. Accompanied by deep understanding of As2O3 in aspect of pharmacology, its application has made considerable progress in solid tumor chemotherapyt. Unfortunately, the clinical application of As2O3 has been restricted by its cardiac toxicity, including QT prolongation, torsades de pointes and sudden cardiac death. The possible mechanisms of As2O3-induced cardiotoxicity are mainly alterations in methylation, generation of reactive oxygen species (ROS), changes in cardiac ion channels and apoptosis. The use of cardioprotective agents together with As2O3 is a alternative approach. Artemisinin (ART), a sesquiterpene lactone isolated from Artemisia annua L (more commonly known as sweet wormwood), usually use as an anti-malarial drug. Evidence is emerging that ART shows pleietrepie characteristic with biological and pharmacologic activities of antiinflammatory, and antioxidant and so forth.In addition, artemisinin could be an effective preventive and therapeutic candidate against cardiac hypertrophy and heart failure. Otherwhile, ART gets attention to several researchers as an anticancer agent and studies show that artemisinin is more cytotoxic to cancer cells than normal cells.The aim of this study is to investigate the combinatory interactive effects of As2O3 with artemisinin and the possible protective effects of artemisinin in As2O3-induced cardiotoxicity in mice.The combinatory interactive effects were evaluated in A549, Hela and HepG2 cell lines. The MTT assay was performed for detecting the cell viability of A549, Hela and HepG2 cells treated with As2O3, artemisinin or the combination of As2O3 and artemisinin for 48 h. In addition, the Isobolograms and combination index (CI) analyses were performed for evaluating whether the two drugs generated a synergistic effect. Wound healing assay was used to investigate the migration rate. Fluorescent microscopy measurements and flow cytometry were carried out to evaluate the apoptosis. The cellular ROS was also detected. The cell proliferation assay in A549, Hela and HepG2 cells indicated that artemisinin significantly enhanced the inhibit effect of As2O3. In addition, the following Isobolograms further demonstrated that combining As2O3 with artemisinin generated synergistic effect. Artemisinin also enhanced the apoptosis, necrosis in As2O3-treated A549 and Hela cells. Artemisinin combined with As2O3 would generate more ROS in Hela cells.In vivo experiment with a mice model, mice were randomly divided into four groups:control group, As2O3 group, artemisinin group, and artemisinin+As2O3 group. Body weight, general condition and mortality of the mice were observed. Electrocardiography was performed before and after the treatment,and serum lactate dehydrogenase (LDH) levels were determined to evaluate heart function. At the end of the study period cardiac tissues were examined histologically and apoptosis assessed. A decrease in body weight, increased LDH activity, prolongation of QT interval and increased myocardial injury were seen in As2O3-treated group compared with the control group. These changs were significantly attenuated by pretreatment with artemisinin. Artemisinin reduced As2O3-induced QT interval prolongation. In artemisinin+As2O3-treated group, artemisinin significantly attenuated cell apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL) and caspase-3 immunohistochemistry assay. These observations suggested that artemisinin has the potential to protect against cardiotoxicity in mice.Combining artemisinin and As2O3 for the clinical anticancer treatment, may achieve a stronger antucancer effect and reduce the cardiotixicity of As2O3. So it could be a meaningful idea of clinical anticancer treatment. But the current study is not consummate enough, the molecular mechanism is not so clear and it needs more penetrating vivo and vitro experiment to verify the value of it for the clinical use.