Solanum nigrum Unripe fruit fraction attenuates Adriamycin resistance by down-regulating multi-drug resistance protein (Mdr)-1 through Jak-STAT pathway.
Solanum nigrum Unripe fruit fraction attenuates Adriamycin resistance by down-regulating multi-drug resistance protein (Mdr)-1 through Jak-STAT pathway.
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DOI：
10.1186/s12906-017-1872-3
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发表时间：
2017-07-18
影响因子：
--
通讯作者：
Asha Nair S
中科院分区：
文献类型：
--
作者：
Jagadeeshan S;David D;Jisha S;Manjula S;Asha Nair S
龙葵是一种常见于温带气候区的草本植物，其成熟的果实具有抗肿瘤作用，是一种传统的民间药材。在传统中医中，它被用于治疗炎症、浮肿、乳房炎和肝癌已有几个世纪的历史，在印度的阿育吠陀传统医药体系中，黑刺被用于治疗肠道疾病、溃疡、腹泻和皮肤病。研究了黑果乙醇提取物(SNME)的抗癌活性及其在NCI/ADR-RES细胞中克服阿霉素耐药的可能机制。用7.8125、15.625、31.2 5、6 2.5、12 5和2 5 0μg/ml的黑木耳甲醇提取物处理NCI/Adr-RES细胞12、2 4和48h，检测细胞活力和增殖情况。用四甲基偶氮唑蓝比色法检测阿霉素单独或与SNME联合作用对细胞生长的影响。细胞周期分析、溴化乙锭和吖啶橙染色、膜联蛋白结合率、核固缩和DNA片段化。为了阐明SNME与多药耐药的关系，我们分析了SNME作用于NCI/ADR-RES细胞后MDR-1、JAK1、STAT3和pSTAT3的表达水平。细胞毒性实验结果表明，黑木耳乙醇糖苷提取物(SNME)的浓度与存活细胞数量呈正相关。SNME与阿霉素联合应用对NCI/ADR-RES细胞具有协同作用，为克服阿霉素耐药提供了第一线证据。DNA片段化、Annexin V细胞凋亡检测和PARP裂解分析结果表明，SNME介导的细胞生长抑制是一种细胞凋亡。从分子水平看，SNME通过下调JAK1、STAT3、pSTAT3和MDR1的表达来抑制JAK-STAT3信号通路，从而超过NCI/ADR-RES细胞的化疗耐药性。综上所述，我们的研究结果表明，龙葵的未成熟果实可能被用作抗阿霉素耐药癌症的化学增敏剂。
Solanum nigrum, herbal plant that commonly grows in temperate climate zone, has been used as a traditional folk medicine whose ripen fruits were proven to exhibit anti-tumor properties. In traditional Chinese medicine, it has been used for centuries to cure inflammation, edema, mastitis and hepatic cancer and in the Ayurvedic system of traditional medicine in India, S. nigrum is applied against enteric diseases, ulcer, diarrhea and skin diseases. A methanolic glycosidic extract fraction of unripe fruit of S. nigrum (SNME) was investigated for its anticancer property and possible mechanism to surmount adriamycin resistance in NCI/ADR-RES cells. The NCI/ADR-RES cells were treated with 7.8125, 15.625, 31.25, 62.5, 125 and 250 μg/ml of methanolic extract of S. nigrum (SNME) for 12, 24 and 48 h, to check the cell viability and proliferation. The cells were also exposed to adriamycin alone or in combination with SNME and the effects on cell growth were determined by MTT. Cell cycle analysis, Ethidium bromide and Acridine orange staining, Annexin-binding efficiency, nuclear condensation and DNA fragmentation of the apoptotic NCI/ADR-RES cells were also determined. To elucidate the relationship between SNME and multi drug resistance, we analyzed the expression levels of Mdr-1, JAK1, STAT3, and pSTAT3 in NCI/ADR-RES cells after treatment with SNME. Results from the cytotoxicity assay showed a direct correlation between the concentration of methanolic glycosidic extract fraction of S. nigrum (SNME) and the surviving cell population. Combination with Adriamycin, SNME exhibits a synergistic action on NCI/ADR-RES cells, giving the first line of evidence to overcoming Adriamycin resistance. The SNME mediated cell growth suppression was proven to be apoptotic, based on results obtained from DNA fragmentation, annexin V apoptosis assaay and PARP cleavage analysis. Looking into the molecular insight SNME surpasses the chemoresistance of NCI/ADR-RES cells by inhibiting the JAK-STAT3 signaling pathway through the down regulation of JAK1, STAT3, pSTAT3, and Mdr1 expression. Collectively our findings suggest that unripe fruit of Solanum nigrum could possibly be used as a chemosensitizing agent against Adriamycin resistant cancers.
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