Abstract
Although bedaquiline has advanced the treatment of multidrug-resistant tuberculosis (TB), concerns remain about the cardiotoxic potential of this agent, albeit by unexplored mechanisms. Accordingly, we have investigated augmentation of the reactivity of human platelets in vitro as a potential mechanism of bedaquiline-mediated cardiotoxicity. Platelet-rich plasma (PRP) or isolated cells prepared from the blood of healthy, adult humans were treated with bedaquiline (0.625–10 µg/ml), followed by activation with adenosine 5’-diphosphate (ADP), thrombin or the thromboxane A2 receptor agonist (U46619). Expression of platelet CD62P (P-selectin), platelet aggregation, Ca2+ fluxes and phosphorylation of Akt1 were measured using flow cytometry, spectrophotometry, fluorescence spectrometry, and by ELISA procedures, respectively. Exposure to bedaquiline caused dose-related inhibition of ADP-activated, but not thrombin- or U46619-activated, expression of CD62P by platelets, achieving statistical significance at a threshold concentration of 5 µg/ml and was paralleled by inhibition of aggregation and Ca2+ mobilization. These ADP-selective inhibitory effects of bedaquiline on platelet activation were mimicked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K), implicating PI3-K as being a common target of both agents, a contention that was confirmed by the observed inhibitory effects of bedaquiline on the phosphorylation of Akt1 following activation of platelets with ADP. These apparent inhibitory effects of bedaquiline on the activity of PI3-K may result from the secondary cationic amphiphilic properties of this agent. If operative in vivo, these anti-platelet effects of bedaquiline may contribute to ameliorating the risk of TB-associated cardiovascular disease, but this remains to be explored in the clinical setting.
Highlights
Inclusion of the diarylquinoline agent, bedaquiline, in chemotherapeutic regimens used in the treatment of multidrug-resistant and extensively drug-resistant (MDR/ XDR)-tuberculosis (TB) has resulted in significantly improved outcomes [1,2,3,4,5]
adenosine 5’-diphosphate (ADP) is an agonist of platelet P2Y1 and P2Y12 receptors and acts as a secondary, autocrine activator of these cells, while thrombin is an agonist of the platelet proteinase-activated receptors 1 and 4 (PAR1/4)
Pre-treatment of platelet-rich plasma (PRP) with wortmannin did not affect the magnitude of either thrombin- or U46619-mediated upregulation of CD62P expression, while pre-treatment with U73122 almost completely attenuated upregulation of CD62P expression mediated by both thrombin and U46619
Summary
Inclusion of the diarylquinoline agent, bedaquiline, in chemotherapeutic regimens used in the treatment of multidrug-resistant and extensively drug-resistant (MDR/ XDR)-tuberculosis (TB) has resulted in significantly improved outcomes [1,2,3,4,5]. Acquisition of insights into the pathogenesis of bedaquiline-associated adverse cardiac events may enable the development of strategies to ameliorate risk This may be of considerable importance since TB per se is associated with a chronic pro-inflammatory/pro-thrombotic state and increased risk of acute cardiovascular events [11] that may be exacerbated in the settings of extended chemotherapy and co-existent co-morbidities [12]. Only very limited data exists with respect to identification of mechanisms that underpin the cardiotoxic potential of bedaquiline In this context, one study has described the potent inhibitory effects of bedaquiline on the activity of the Kv.11.1 channel [4], which mediates the repolarizing current in the cardiac action potential. The clinical relevance of this study, which was undertaken using Kv.11.1 channel-transfected hamster embryonic kidney cells in vitro, remains to be established [4]
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