Tetrandrine Enhances The Anticancer Effects Of Arsenic Trioxide And Decreases Its Cardiotoxicity

Arsenic trioxide is a chemotherapy drug that widely used in the clinical treat of acute promyelocytic leukemia (APL). However, because of the less sensitivity of solid tumors to arsenic trioxide than acute promyelocytic leukemia, and the cardiac toxicity induced by arsenic trioxide, including the heart cell damage which results in calcium overload, and acquired QT interval prolong syndrome, which can cause atrioventricular fibrillation and torsades de pointes tachycardia and other serious consequences. Tetrandrine, is a double benzyl isoquinoline alkaloid, extract from tetrandra. Tetrandrine is a calcium channel blocker, has been reported to potent the abilities of against calcium overload, anti-inflammatory effect and can reduce QT interval prolongation. Meanwhile, Tetrandrine also has anti-cancer effect, it can enhance effects of other anti-cancer chemotherapeutic drugs. Therefore, we attempted to use the combination of arsenic trioxide and Tetrandrine in antitumor therapy, to increase the anti-tumor effects of arsenic trioxide and reduce its cardiotoxicity.In the vitro model of A549, HepG2and Hela cells, the MTT assay proved Tetrandrine can significantly enhance the anti-proliferation of arsenic trioxide, and the effect is in dose-dependent and time-dependent manner. The Isobolograms further proved that arsenic trioxide combining with tetrandrine gernerated synergistic anti-cancer effects on A549and HepG2cells, and an addictive effect in Hela cells.Further investigate in HepG2cells were performed to test apoptosis. Through fluorescence microscopy with AO stained and flow cytometry after the Annexin V-Pi staining, tetrandrine can significantly enhance arsenic trioxide-induced apoptosis and necrosis. After PI staining and flow cytometry analysis, it can be found that after trating with Tetndrine and arsenic trioxide, HepG2cell’s cell cycle changed, the cell population in S phase decreased. A conclusion has been put out:Tetrandrine can enhance arsenic trioxide-induced apoptosis and necrosis as well as changes in the cell cycle to enhance the anticancer effects of arsenic trioxide.In vivo experiment with a model of mice, lmg/kg/d30days of arsenic trioxide by intraperitoneal injection to mice significantly prolong the ECG QTc interval, and cause fibrillation, serum AST and ASL content also increased. In HE sections of their heart tissue, we found much inflammatory cells, cells are disorder and degeneration. While mice were treated with50mg/kg/d (i.p.) Tetrandrine and lmg/kg/d arsenic trioxide, these QTc intervals were shorter than the arsenic trioxide group, and less fibrillation. Serum AST and ALT levels were also lower than arsenic trioxide group, while heart HE sections showed that in the combination group, the cardiac cells arranged more orderly, normal cell morphology, and fewer inflammatory cells. So, it can be proved that Tetrandrine can reduce the cardiotoxicity caused by arsenic trioxide.Combining Tetrandrine with arsenic trioxide for the clinical anti-cancer treatment, may not only achieve a stronger anti-cancer effect, but also reduce the cardiotoxicity of arsenic trioxide, which could be a meaningful new idea of clinical anti-cancer treatment. However, the current study is not comprehensive enough, the specific molecular mechanism is not clear, it needs more in-depth vitro and vivo experimental data to verify the value of its value for clinical use.