Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.
Cell Death Dis. 2022 Jun 2;13(6):521. doi: 10.1038/s41419-022-04974-8.
Carboplatin is the most used first-line drug for the treatment of human retinoblastoma (RB), a rare form of cancer in infancy and childhood. However, the clinical application of carboplatin is restricted due to the emergence of acquired multi-drug resistance (MDR) after long-term treatment. Here, we report a new strategy to eliminate MDR RB cells by inducing autophagy-dependent ferroptosis. Compared with parent cells, carboplatin-resistant human RB cells have higher autophagy activity, which drives the formation of MDR to other chemotherapeutic drugs (e.g., etoposide and vincristine). In addition to confirming the traditional strategy of inhibiting autophagy to overcome MDR, we also establish an approach of inducing selective ferritinophagy to eliminate drug-resistant cells. We evaluate the effectiveness and safety of 4-octyl itaconate, a cell-permeable derivative of the metabolite itaconate, in inducing ferritinophagy-dependent ferroptosis in the treatment of MDR RB cells in vitro and in xenograft mouse models. These findings may provide essential clues for initiating clinical trials that target autophagy-dependent ferroptosis to kill drug-tolerant persistent cells during RB therapy.
卡铂是治疗人类视网膜母细胞瘤（RB）的最常用一线药物，RB 是一种罕见的婴幼儿期癌症。然而，由于长期治疗后出现获得性多药耐药（MDR），卡铂的临床应用受到限制。在这里，我们报告了一种通过诱导自噬依赖性铁死亡来消除 MDR RB 细胞的新策略。与亲本细胞相比，卡铂耐药的人 RB 细胞具有更高的自噬活性，这促使它们对其他化疗药物（如依托泊苷和长春新碱）产生 MDR。除了证实抑制自噬以克服 MDR 的传统策略外，我们还建立了一种诱导选择性铁蛋白自噬以消除耐药细胞的方法。我们评估了代谢物衣康酸的细胞通透衍生物 4-辛基衣康酸在体外诱导铁蛋白自噬依赖性铁死亡以及在异种移植小鼠模型中治疗 MDR RB 细胞中的有效性和安全性。这些发现可能为启动临床试验提供重要线索，这些临床试验旨在通过靶向自噬依赖性铁死亡来杀死 RB 治疗过程中耐受药物的持续细胞。
