Department of Surgery, St George Hospital, 4-10 South Street, Kogarah, Sydney 2217, NSW, Australia.
J Exp Clin Cancer Res. 2014 Nov 12;33(1):92. doi: 10.1186/s13046-014-0092-7.
Bromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years. As such, the potential values of these agents in cancer therapy have been variably reported in the literature. In the present study, the efficacy of bromelain and N-acetylcysteine in single agent and combination treatment of human gastrointestinal carcinoma cells was evaluated in vitro and the underlying mechanisms of effect were explored.
The growth-inhibitory effects of bromelain and N-acetylcysteine, on their own and in combination, on a panel of human gastrointestinal carcinoma cell lines, including MKN45, KATO-III, HT29-5F12, HT29-5M21 and LS174T, were assessed by sulforhodamine B assay. Moreover, the influence of the treatment on the expression of a range of proteins involved in the regulation of cell cycle and survival was investigated by Western blot. The presence of apoptosis was also examined by TUNEL assay.
Bromelain and N-acetylcysteine significantly inhibited cell proliferation, more potently in combination therapy. Drug-drug interaction in combination therapy was found to be predominantly synergistic or additive. Mechanistically, apoptotic bodies were detected in treated cells by TUNEL assay. Furthermore, Western blot analysis revealed diminution of cyclins A, B and D, the emergence of immunoreactive subunits of caspase-3, caspase-7, caspase-8 and cleaved PARP, withering or cleavage of procaspase-9, overexpression of cytochrome c, reduced expression of anti-apoptotic Bcl-2 and pro-survival phospho-Akt, the emergence of the autophagosomal marker LC3-II and deregulation of other autophagy-related proteins, including Atg3, Atg5, Atg7, Atg12 and Beclin 1. These results were more prominent in combination therapy.
We report for the first time to our knowledge the growth-inhibitory and cytotoxic effects of bromelain and N-acetylcysteine, in particular in combination, on a panel of gastrointestinal cancer cell lines with different phenotypes and characteristics. These effects apparently resulted from cell cycle arrest, apoptosis and autophagy. Towards the development of novel strategies for the enhancement of microscopic cytoreduction, our results lay the basis for further evaluation of this formulation in locoregional approaches to peritoneal surface malignancies and carcinomatosis.
菠萝蛋白酶和 N-乙酰半胱氨酸是两种天然含巯基化合物，安全性良好，五十多年来一直被研究用于健康和疾病领域的益处和应用。因此，这些药物在癌症治疗中的潜在价值在文献中有不同的报道。在本研究中，评估了菠萝蛋白酶和 N-乙酰半胱氨酸单独和联合治疗人胃肠道癌细胞系的疗效，并探讨了其作用的潜在机制。
通过磺酰罗丹明 B 测定法评估菠萝蛋白酶和 N-乙酰半胱氨酸单独及联合对一组人胃肠道癌细胞系（包括 MKN45、KATO-III、HT29-5F12、HT29-5M21 和 LS174T）的生长抑制作用。此外，通过 Western blot 检测治疗对细胞周期和存活调节相关蛋白表达的影响。通过 TUNEL 检测也检查了凋亡的存在。
菠萝蛋白酶和 N-乙酰半胱氨酸显著抑制细胞增殖，联合治疗作用更强。联合治疗中的药物相互作用主要为协同或相加。通过 TUNEL 检测在处理细胞中检测到凋亡小体。此外，Western blot 分析显示，凋亡小体中检测到 cyclins A、B 和 D 减少，caspase-3、caspase-7、caspase-8 和 cleaved PARP 的免疫反应性亚单位出现，procaspase-9 减少或裂解，细胞色素 c 过表达，抗凋亡 Bcl-2 和促生存磷酸化 Akt 减少，自噬小体标记物 LC3-II 的出现，以及其他自噬相关蛋白（包括 Atg3、Atg5、Atg7、Atg12 和 Beclin 1）的失调。这些结果在联合治疗中更为明显。
我们首次报道了菠萝蛋白酶和 N-乙酰半胱氨酸对一组具有不同表型和特征的胃肠道癌细胞系的生长抑制和细胞毒性作用，尤其是联合用药。这些作用显然是由于细胞周期停滞、细胞凋亡和自噬引起的。为了开发增强微观细胞减灭的新策略，我们的结果为进一步评估该制剂在局部区域治疗腹膜表面恶性肿瘤和癌性播散中的应用奠定了基础。
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