University Children's Hospital, Department of Pediatric Surgery and Pediatric Urology, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany.
Exp Cell Res. 2014 Mar 10;322(1):217-25. doi: 10.1016/j.yexcr.2013.12.007. Epub 2013 Dec 16.
Drug resistance and metastasis remain major challenges in the treatment of high-risk hepatoblastoma (HB) and require the development of alternative therapeutic strategies. Modulation of apoptosis in HB cells enhances the sensitivity of these cells towards various drugs and has been discussed to enforce treatment. We investigated the impact of apoptosis sensitisers, BH3-mimetics, on the interaction between the host and HB to reduce tumour growth and dissemination while enhancing immunity. BH3-mimetics, such as obatoclax and ABT-737, enhanced the apoptosis-inducing effect of TRAIL and TNF-α resistant HB cells (HepT1 and HUH6). Tumour cell migration was inhibited by ABT-737 and more markedly by obatoclax. In an orthotopic model of HB, tumour uptake was reduced when the cells were pretreated with low concentrations of obatoclax. Only 1 of 7 mice developed HB in the liver, compared with an incidence of 0.8 in the control group. In summary, our study showed that apoptosis sensitisers had broader effects on HB cells than expected including migration and susceptibility to cytokines in addition to the known effects on drug sensitization. Sensitising HB to apoptosis may also allow resistant HB to be targeted by immune cells and prevent tumour cell dissemination.
耐药性和转移仍然是高危肝母细胞瘤 (HB) 治疗的主要挑战，需要开发替代治疗策略。HB 细胞中凋亡的调节增强了这些细胞对各种药物的敏感性，并已被讨论用于增强治疗效果。我们研究了凋亡敏化剂 BH3 模拟物对宿主和 HB 之间相互作用的影响，以减少肿瘤生长和扩散，同时增强免疫力。BH3 模拟物，如 obatoclax 和 ABT-737，增强了 TRAIL 和 TNF-α 耐药 HB 细胞（HepT1 和 HUH6）的凋亡诱导作用。ABT-737 和更明显的 obatoclax 抑制肿瘤细胞迁移。在 HB 的原位模型中，当用低浓度的 obatoclax 预处理细胞时，肿瘤摄取减少。与对照组的 0.8 相比，只有 7 只小鼠中有 1 只在肝脏中发生 HB。总之，我们的研究表明，凋亡敏化剂对 HB 细胞的作用比预期的更广泛，包括除了对药物敏化作用外，还包括迁移和对细胞因子的敏感性。使 HB 对凋亡敏感也可以使耐药的 HB 细胞被免疫细胞靶向，并防止肿瘤细胞扩散。
