Müller Alena, Barat Samarpita, Chen Xi, Bui Khac Cuong, Bozko Przemyslaw, Malek Nisar P, Plentz Ruben R
Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
Int J Oncol. 2016 May;48(5):2025-34. doi: 10.3892/ijo.2016.3411. Epub 2016 Mar 1.
Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra- and extrahepatic human CC cell lines. The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analyzed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFκB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial-mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment. Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFκB on CC cells indicated that bromelain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFκB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC.
胆管癌（CC）是全球最常见的胆道恶性肿瘤，预后较差，因此需要新的全身治疗方法。菠萝蛋白酶和木瓜蛋白酶等植物提取物是来自菠萝和木瓜果实的半胱氨酸蛋白酶，已知具有抗肿瘤活性。因此，在本研究中，我们首次研究了菠萝蛋白酶和木瓜蛋白酶对肝内和肝外人类胆管癌细胞系的抗癌作用。使用细胞增殖、伤口愈合、侵袭和凋亡检测以及蛋白质印迹法分析了菠萝蛋白酶和木瓜蛋白酶对人类胆管癌细胞生长、迁移、侵袭和上皮可塑性的影响。菠萝蛋白酶和木瓜蛋白酶导致胆管癌细胞的增殖、侵袭和迁移减少。两种植物提取物均抑制NFκB/AMPK信号通路及其下游信号蛋白，如p-AKT、p-ERK、p-Stat3。此外，部分发现MMP9和其他上皮-间质转化标志物下调。菠萝蛋白酶和木瓜蛋白酶处理后诱导了细胞凋亡。有趣的是，与木瓜蛋白酶相比，菠萝蛋白酶对胆管癌的抑制作用总体上更有效。siRNA介导的胆管癌细胞中NFκB沉默表明，菠萝蛋白酶和木瓜蛋白酶对人类胆管癌细胞系具有细胞毒性作用，相比之下，菠萝蛋白酶和部分木瓜蛋白酶通过NFκB/AMPK信号通路损害肿瘤生长。特别是菠萝蛋白酶可能成为一种有前景的潜在治疗选择，为人类胆管癌的治疗开辟新的思路。
