Dallons Matthieu, Schepkens Corentin, Dupuis Aurélie, Tagliatti Vanessa, Colet Jean-Marie
Department of Human Biology and Toxicology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium.
Front Pharmacol. 2020 Feb 20;11:79. doi: 10.3389/fphar.2020.00079. eCollection 2020.
Doxorubicin (DOX) is an anticancer drug widely used in oncology. The main limitation to DOX treatments though is due to the cumulative dose that may lead to cardiotoxicity. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure consecutive to a progressive loss in cardiomyocytes due to cell necrosis and apoptosis induced by DOX. For many years, the cardiac oxidative stress caused by DOX was considered as its main toxic mechanism. Therefore, several clinical trials were carried out to assess the efficacy of various antioxidants as a cardioprotective strategy. Only dexrazoxane (DEX), did significantly reduce DOX cardiotoxicity. However, since other antioxidants used later on to counteract DOX cardiotoxicity were not as successful as DEX, DOX-induced oxidative stress and DEX antioxidant activity are not considered as the main feature anymore and this led the scientific world to suspect other involved mechanisms which are still unknown. The objective of the present work was to study from a metabolic point of view the side effects of DOX and the protective properties of DEX. H-NMR metabonomics was applied to the rat cardiomyoblastic H9C2 cell line. This strategy was used with the hope of unveiling possible new targets to cope with DOX cardiotoxicity. Another underlying goal was the validation of H9C2 model for metabolic investigations of DOX and DEX effects. For this purpose, several parameters, including oxidative stress, cell mortality, and apoptosis, were measured to assess the effects of DOX and DEX alone or in combination. The metabonomic study was carried out on cellular fluids collected after either 4 or 24 hours of DOX-exposure. Under such experimental conditions, both the major adverse effects reported in patients exposed to DOX and the protective effect of DEX were demonstrated suggesting that the H9C2 model is relevant to investigate both DOX cardiotoxicity and putative cardioprotective strategies. In addition, the metabonomics findings highlighted several metabolic pathways involved in DOX cardiotoxicity and DEX cardioprotective effects as potential metabolic targets for cardioprotection: energy metabolism, redox balance, as well as phospholipids and proteins metabolism.
阿霉素（DOX）是一种广泛应用于肿瘤学的抗癌药物。然而，DOX治疗的主要局限性在于其累积剂量可能导致心脏毒性。临床上，DOX诱导的心肌病表现为进行性心力衰竭，这是由于DOX诱导的细胞坏死和凋亡导致心肌细胞逐渐丧失所致。多年来，DOX引起的心脏氧化应激被认为是其主要毒性机制。因此，开展了多项临床试验来评估各种抗氧化剂作为心脏保护策略的疗效。只有右丙亚胺（DEX）能显著降低DOX的心脏毒性。然而，由于后来用于对抗DOX心脏毒性的其他抗氧化剂不如DEX成功，DOX诱导的氧化应激和DEX的抗氧化活性不再被视为主要特征，这使得科学界怀疑还有其他未知的相关机制。本研究的目的是从代谢角度研究DOX的副作用和DEX的保护特性。将氢核磁共振代谢组学应用于大鼠心肌母细胞H9C2细胞系。采用这一策略希望能揭示应对DOX心脏毒性的可能新靶点。另一个潜在目标是验证H9C2模型用于DOX和DEX作用的代谢研究。为此，测量了包括氧化应激、细胞死亡率和凋亡在内的几个参数，以评估DOX和DEX单独或联合使用的效果。代谢组学研究在DOX暴露4小时或24小时后收集的细胞液上进行。在这样的实验条件下，暴露于DOX的患者中报告的主要不良反应和DEX的保护作用均得到了证实，这表明H9C2模型与研究DOX心脏毒性和假定的心脏保护策略相关。此外，代谢组学研究结果突出了DOX心脏毒性和DEX心脏保护作用中涉及的几个代谢途径，作为心脏保护的潜在代谢靶点：能量代谢、氧化还原平衡以及磷脂和蛋白质代谢。
