Arsenic trioxide (As 2 O 3 ) produces dramatic remissions in patients with relapsed or refractory acute promyelocytic leukemia. Its clinical use is burdened by QT prolongation, torsade de pointes, and sudden cardiac death. In the present study, we analyzed the molecular mechanisms leading to As 2 O 3 -induced abnormalities of cardiac electrophysiology. Using biochemical and electrophysiological methods, we show that long-term exposure to As 2 O 3 increases cardiac calcium currents and reduces surface expression of the cardiac potassium channel human ether-a-go-go-related gene (HERG) at clinically relevant concentrations of 0.1 to 1.5 M. In ventricular myocytes, As 2 O 3 increases action potential duration measured at 30 and 90% of repolarization. As 2 O 3 interferes with hERG trafficking by inhibition of hERG-chaperone complexes and increases calcium currents by a faster cellular process. We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As 2 O 3 . Our results suggest that calcium-channel antagonists will be useful in normalizing QT prolongation during As 2 O 3 therapy. As 2 O 3 is the first example of a drug that produces hERG liability by inhibition of ion-channel trafficking. Other drugs that interfere with proteins in the processing pathway of cardiac ion channels may be proarrhythmic for similar reasons.

Aconitine is a well-known arrhythmogenic toxin and induces triggered activities through cardiac voltage-gated Na+ channels. However, the effects of aconitine on intracellular Ca2+ signals were previously unknown. We investigated the effects of aconitine on intracellular Ca2+ signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca2+ signals were evaluated by measuring L-type Ca2+ currents, caffeine-induced Ca2+ release and the expression of NCX and SERCA2a. Action potential and triggered activities were recorded by whole-cell patch-clamp techniques. In rat ventricular myocytes, the action potential duration was significantly prolonged by 1 µM aconitine. At higher concentrations (5 µM and 10 µM), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 µM) significantly increased the ICa-L density from 12.77 ± 3.12 pA/pF to 18.98 ± 3.89 pA/pF (n=10, p<0.01). The activation curve was shifted towards more negative potential, while the inactivation curve was shifted towards more positive potential by 1 μM aconitine. The level of Ca2+ release induced by 10 mM caffeine was markedly increased. Aconitine (1 µM) increased the expression of NCX, while SERCA2a expression was reduced. In conclusion, aconitine increased the cytosolic [Ca2+]i by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca2+]i induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca2+ signals.

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Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases that includes visceral leishmaniasis, or Kala Azar. Chemotherapy with trivalent potassium antimony tartrate (PAT) and, more importantly, pentavalent antimony-carbohydrate complexes, such as sodium stibogluconate (SSG), has been reported to prolong the QT interval and produce life-threatening arrhythmias. PAT is chemically related to As 2 O 3 , which alters cardiac excitability by inhibition of human ether a-go-go related gene (hERG) trafficking and an increase of cardiac calcium currents. In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC 50 , 11.8 M) and inhibits hERG maturation on Western blots (IC 50 , 62 M). Therapeutic concentrations of 0.3 M PAT increase cardiac calcium currents from Ϫ4.8 Ϯ 0.7 to Ϫ7.3 Ϯ 0.5 pA/pF at 10 mV. In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/I Kr or any other cardiac potassium current at therapeutic concentrations. However, both cardiac sodium and calcium currents were significantly increased on long-term exposure to 30 M SSG in isolated guinea pig ventricular myocytes. We propose that the increase in calcium currents from Ϫ3.2 Ϯ 0.3 to Ϫ5.1 Ϯ 0.3 pA/pF at 10 mV prolongs APD 90 from 464 Ϯ 35 to 892 Ϯ 64 ms. Our data suggest that conversion of Sb(V) into active Sb(III) in patients produces a common mode of action for antimonial drugs, which define a novel compound class that increases cardiac risk not by a reduction of hERG/I Kr currents but-for the first time-by an increase in cardiac calcium currents.

We presented an antibiotic-loaded c-cyclodextrin metal-organic framework that delivered antibiotics suitable for the treatment of bacterial infections. The c-cyclodextrin metal-organic framework was developed using c-cyclodextrin and potassium ion via the ultrasonic method. The antibiotic (florfenicol and enrofloxacin) was primarily encapsulated into the pore structures of c-CD-MOF, which allowed the sustained release of antibiotics over an extended period of time in vitro and in vivo. Notably, antibiotics-loaded c-CD-MOF showed much superior activity against bacteria than free antibiotics (lower MIC value) and displayed better long-lasting activity (longer antibacterial time). The antibiotics-loaded c-CD-MOF showed nontoxic and perfect biocompatibility to mammalian cells and tissues both in vitro and in vivo. These materials thus represent a novel drug-delivery device suitable for antibiotic therapy. This research is of great significance for reducing the generation of bacterial resistance and providing new ideas for the application of c-CD-MOF.