Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5R 0A3, Canada.
Int J Mol Sci. 2023 Jul 27;24(15):12052. doi: 10.3390/ijms241512052.
Neuroblastoma is the most common tumour in children under 1 year old, accounting for 12-15% of childhood cancer deaths. Although current treatments are relatively efficacious against this cancer, associated adverse effects could be detrimental to growth and development. In contrast, glioblastoma accounts for 52% of brain tumours and has an extremely poor prognosis. Current chemotherapeutics include temozolomide, which has numerous negative side-effects and a low-effective rate. Previous studies have shown the manipulation of autophagy to be a promising method for targeting cancers, including glioblastoma. We sought to determine the effects of autophagic alterations in combination with current chemotherapies in both neuroblastoma and glioblastoma. Supplementing cisplatin or temozolomide with autophagy activator rapamycin stabilized cancer cell mitochondria, despite having little effect on apoptosis or oxidative stress. Autophagy inhibition via 3-methyladenine or hydroxychloroquine alongside standard chemotherapies enhanced apoptosis and oxidative stress, with 3-methyladenine also disrupting mitochondrial health. Importantly, combining hydroxychloroquine with 0.5 µM cisplatin or 50 µg/mL temozolomide was as or more effective than 2 µM cisplatin or 100 µg/mL temozolomide alone. Analyzing these interesting results, a combined treatment of autophagy inhibitor with a standard chemotherapeutic agent could help to improve patient prognosis and reduce chemotherapy doses and their associated side-effects.
神经母细胞瘤是 1 岁以下儿童中最常见的肿瘤，占儿童癌症死亡人数的 12-15%。尽管目前的治疗方法对这种癌症相对有效，但相关的不良反应可能对生长和发育有害。相比之下，胶质母细胞瘤占脑肿瘤的 52%，预后极差。目前的化疗药物包括替莫唑胺，它有许多负面副作用和低有效率。先前的研究表明，操纵自噬是针对癌症（包括胶质母细胞瘤）的一种有前途的方法。我们试图确定自噬改变与目前的化疗联合应用于神经母细胞瘤和胶质母细胞瘤的效果。补充顺铂或替莫唑胺与自噬激活剂雷帕霉素稳定了癌细胞的线粒体，尽管对细胞凋亡或氧化应激几乎没有影响。通过 3-甲基腺嘌呤或羟氯喹联合标准化疗抑制自噬增强了细胞凋亡和氧化应激，3-甲基腺嘌呤还破坏了线粒体的健康。重要的是，将羟氯喹与 0.5 µM 顺铂或 50 µg/mL 替莫唑胺联合使用的效果与单独使用 2 µM 顺铂或 100 µg/mL 替莫唑胺相同或更好。分析这些有趣的结果表明，自噬抑制剂与标准化疗药物的联合治疗可能有助于改善患者的预后，并减少化疗药物剂量及其相关的副作用。
