Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways.
Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways.
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DOI：
10.1016/j.taap.2014.10.008
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发表时间：
2014-12-01
影响因子：
3.8
通讯作者：
Shi, Xianglin
中科院分区：
文献类型：
--
作者：
Pratheeshkumar, Poyil;Son, Young-Ok;Divya, Sasidharan Padmaja;Roy, Ram Vinod;Hitron, John Andrew;Wang, Lei;Kim, Donghern;Dai, Jin;Asha, Padmaja;Zhang, Zhuo;Wang, Yitao;Shi, Xianglin
六价铬[Cr(VI)]是一种众所周知的人类致癌物，与肺癌的发病有关。通过膳食抗氧化剂抑制金属诱导的致癌作用是一种新方法。木犀草素是一种存在于水果和蔬菜中的天然膳食类黄酮，具有有效的抗氧化和抗炎活性。我们发现，人支气管上皮细胞 (BEAS-2B) 短期暴露于 Cr(VI) (5 μM) 后，ROS 生成、NADPH 氧化酶 (NOX) 激活、脂质过氧化和谷胱甘肽消耗显着增加，而木犀草素处理以剂量依赖性方式显着抑制这些现象。木犀草素处理可降低 BEAS-2B 细胞中由 Cr(VI) 诱导的 AP-1、HIF-1α、COX-2 和 iNOS 启动子活性。此外，木犀草素还可以保护 BEAS-2B 细胞免受慢性 Cr(VI) 暴露诱导的恶性转化。此外，木犀草素还抑制慢性 Cr(VI) 暴露的 BEAS-2B 细胞中促炎细胞因子（IL-1β、IL-6、IL-8、TNF-α）和 VEGF 的产生。蛋白质印迹分析显示，在慢性 Cr(VI) 暴露的 BEAS-2B 细胞中，木犀草素可抑制与生存（Akt、Fak、Bcl-2、Bcl-xL）、炎症（MAPK、NF-κB、COX-2、STAT-3、iNOS、TNF-α）和血管生成（HIF-1α、VEGF、MMP-9）相关的多种基因产物。与单独的 Cr(VI) 治疗组相比，在木犀草素存在下长期暴露于 Cr(VI) 的 BEAS-2B 细胞注射裸鼠的肿瘤发病率降低。过氧化氢酶 (CAT) 或 SOD2 的过度表达可消除 Cr(VI) 诱导的恶性转化。总体而言，我们的结果表明，木犀草素通过清除 ROS 并调节与 ROS 相关的多种细胞信号传导机制，保护 BEAS-2B 细胞免受 Cr(VI) 诱导的癌变。因此，木犀草素可作为一种潜在的化学预防剂，对抗 Cr(VI) 诱导的致癌作用。
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis.
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影响因子：
10.4
作者：
Beaver LM;Stemmy EJ;Schwartz AM;Damsker JM;Constant SL;Ceryak SM;Patierno SR
通讯作者：
Patierno SR
影响因子：
--
作者：
Bartsch, H;Nair, J
通讯作者：
Nair, J
影响因子：
3.9
作者：
Ahmad, Mir Kaisar;Syma, Syed;Mahmood, Riaz
通讯作者：
Mahmood, Riaz
影响因子：
4.7
作者：
Chen, JY;Yan, Y;Huang, CS
通讯作者：
Huang, CS
影响因子：
3.8
作者：
Beaver LM;Stemmy EJ;Constant SL;Schwartz A;Little LG;Gigley JP;Chun G;Sugden KD;Ceryak SM;Patierno SR
通讯作者：
Patierno SR