Carles Liliana, Gibaja Alejandro, Scheper Verena, Alvarado Juan C, Almodovar Carlos, Lenarz Thomas, Juiz José M
Instituto de Investigación en Discapacidades Neurológicas (IDINE), School of Medicine, Universidad de Castilla-La Mancha (UCLM), Campus in Albacete, 02008 Albacete, Spain.
Department of Otolaryngology, University Hospital "Doce de Octubre", 28041 Madrid, Spain.
Antioxidants (Basel). 2024 Jun 24;13(7):761. doi: 10.3390/antiox13070761.
Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg administered alone, as MgSO, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined "antioxidation threshold", results in unrecoverable redox imbalance with loss of otoprotectant activity.
顺铂是一种用于多种癌症治疗的化疗药物。它对肿瘤细胞的细胞毒性同样也发生在健康细胞和组织中，从而导致严重的不良事件。其中一种非常常见的不良事件是耳毒性，会导致听力损失，这可能会在肿瘤治疗成功后永久性地影响生活质量。加剧的氧化应激是顺铂包括耳毒性在内的主要细胞毒性机制。先前的报道显示抗氧化剂可预防顺铂耳毒性，但缺乏关于抗氧化剂配方的耳保护活性和机制的比较研究。在此，我们证明，先前已证明可预防噪声性听力损失的维生素A、C和E与镁的混合物（ACEMg），可逆转顺铂治疗后大鼠的听觉阈值变化，促进外毛细胞存活，并减轻耳蜗中的氧化应激，从而预防顺铂引起的严重耳毒性。向ACEMg配方中添加500毫克N-乙酰半胱氨酸（NAC）（单独使用时也显示出对顺铂耳毒性有显著减轻作用）会导致ACEMg耳保护功能退化。单独以硫酸镁形式给药的镁也可预防顺铂耳毒性，但与500毫克NAC联合使用时，耳保护作用也会大大降低。与500毫克NAC相比，将NAC剂量增加到1000毫克也会导致耳保护活性急剧丧失。这些发现支持单一抗氧化剂或抗氧化剂组合，特别是本实验系列中的ACEMg，对顺铂耳毒性具有显著的耳保护功效。然而，过量的联合抗氧化剂和/或高于尚未确定的“抗氧化阈值”的剂量会导致不可恢复的氧化还原失衡，并丧失耳保护活性。
