Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: significance of combination therapy.
Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: significance of combination therapy.
复制标题
DOI：
10.1186/s13046-014-0092-7
复制
发表时间：
2014-11-12
期刊：
影响因子：
--
通讯作者：
Morris DL
中科院分区：
文献类型：
--
作者：
Amini A;Masoumi-Moghaddam S;Ehteda A;Morris DL
菠萝蛋白酶和 N-乙酰半胱氨酸是两种天然的含巯基化合物，具有良好的安全性，对其在健康和疾病方面的益处和应用进行了五十多年的研究。因此，文献中对这些药物在癌症治疗中的潜在价值有不同的报道。本研究在体外评价了菠萝蛋白酶和N-乙酰半胱氨酸单药和联合治疗人胃肠道癌细胞的疗效，并探讨了其作用的潜在机制。通过磺胺罗丹明 B 测定评估了菠萝蛋白酶和 N-乙酰半胱氨酸单独和组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，通过蛋白质印迹研究了治疗对一系列参与细胞周期和存活调节的蛋白质表达的影响。还通过TUNEL测定检查细胞凋亡的存在。菠萝蛋白酶和 N-乙酰半胱氨酸显着抑制细胞增殖，联合治疗效果更佳。发现联合治疗中的药物间相互作用主要是协同作用或相加作用。从机制上讲，通过 TUNEL 测定在处理的细胞中检测到凋亡小体。此外，蛋白质印迹分析显示细胞周期蛋白 A、B 和 D 减少，caspase-3、caspase-7、caspase-8 和裂解 PARP 的免疫反应亚基出现，procaspase-9 枯萎或裂解，细胞色素 c 过度表达，抗凋亡 Bcl-2 和促存活磷酸-Akt 表达减少，自噬体标记物出现LC3-II 和其他自噬相关蛋白的失调，包括 Atg3、Atg5、Atg7、Atg12 和 Beclin 1。这些结果在联合治疗中更为突出。据我们所知，我们首次报告了菠萝蛋白酶和 N-乙酰半胱氨酸（特别是组合）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。这些效应显然是由细胞周期停滞、细胞凋亡和自噬引起的。为了开发增强显微细胞减灭术的新策略，我们的结果为进一步评估该制剂在腹膜表面恶性肿瘤和癌病局部治疗中的应用奠定了基础。
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.
登录
查看更多内容
DOI：
10.1016/0006-291x(80)91147-x
发表时间：
1980-01-01
影响因子：
3.1
作者：
BERRIGAN, MJ;GURTOO, HL;MARINELLO, AJ
通讯作者：
MARINELLO, AJ
影响因子：
4.7
作者：
DEFLORA, S;BENNICELLI, C;DEFLORA, A
通讯作者：
DEFLORA, A
影响因子：
6.1
作者：
Deshpande, V. S.;Kehrer, James P.
通讯作者：
Kehrer, James P.
影响因子：
5.2
作者：
Brum G;Carbone T;Still E;Correia V;Szulak K;Calianese D;Best C;Cammarata G;Higgins K;Ji F;Di W;Wan Y
通讯作者：
Wan Y
影响因子：
6
作者：
Bhui, Kulpreet;Tyagi, Shilpa;Shukla, Yogeshwer
通讯作者：
Shukla, Yogeshwer