Department of Surgery, University of New South Wales, St George Hospital, Kogarah, New South Wales, Australia.
Anticancer Drugs. 2014 Feb;25(2):150-60. doi: 10.1097/CAD.0000000000000039.
Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3-5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.
恶性腹膜间皮瘤（MPM）是一种罕见的腹膜间皮肿瘤，与石棉暴露有关。由于症状不典型且诊断较晚，患者生存状况较差（<1 年）。细胞减灭术和腹腔热灌注化疗的治疗方法改善了部分患者的生存状况（中位数 3-5 年）。因此，迫切需要新的治疗方法。MUC1 是一种糖基化依赖性蛋白，使肿瘤具有侵袭性、转移性和化疗耐药性。菠萝蛋白酶（半胱氨酸蛋白酶）水解糖苷键。因此，我们研究了菠萝蛋白酶对表达 MUC1 的 MPM 细胞系的抗肿瘤作用。使用载玻片上生长的细胞的免疫荧光探针和细胞裂解物的 Western blot 分析评估细胞中的 MUC1 表达。用不同浓度的菠萝蛋白酶处理细胞系，4 和 72 小时后，用标准磺酰罗丹明测定法评估细胞活力。还将细胞与细胞毒性药物（顺铂或 5-FU）联合处理，并在 72 小时时评估其活力。最后，通过 Western blot 分析研究了菠萝蛋白酶对细胞存活蛋白的影响。PET 细胞比 YOU 细胞表达更多的 MUC1。菠萝蛋白酶对 PET 和 YOU 细胞的细胞活力均产生不良影响，而 PET 细胞略有耐药性。在两种细胞系中，菠萝蛋白酶的添加显著增加了顺铂的细胞毒性。然而，5-FU 与菠萝蛋白酶联合使用并没有显示出任何明显增加的细胞毒性。菠萝蛋白酶诱导的细胞死亡是通过细胞凋亡和自噬发生的。菠萝蛋白酶具有作为 MPM 治疗剂开发的潜力。
