College of Pharmacy and Medical Research Center, Chungbuk National University, 52 Naesudong-ro, Heungdeok-gu, Cheongju, Chungbuk 361-763, Korea.
Department of Obstetrics and Gynecology, Daejeon St. Mary's Hospital, College of Medicine, the Catholic University of Korea, 64 Daeheung-ro, Jung-gu, Daejeon 301-723, Korea.
Toxins (Basel). 2014 Jul 25;6(8):2210-28. doi: 10.3390/toxins6082210.
Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB) activity assay. BV (1-5 μg/mL) inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax) was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF)-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.
我们之前的研究结果表明，蜂毒（BV）在几种癌细胞中具有抗癌活性。然而，BV 对肺癌细胞生长的影响尚未报道。用台盼蓝摄取、软琼脂形成以及 DAPI 和 TUNEL 检测法测定细胞活力。用 Western blot 法测定细胞死亡相关蛋白表达。用 EMSA 测定核因子 κB（NF-κB）活性。BV（1-5μg/mL）以剂量依赖的方式诱导肺癌细胞系 A549 和 NCI-H460 中的细胞凋亡，从而抑制肺癌细胞的生长。与细胞凋亡一致，DR3 和 DR6 的表达明显增加。然而，通过小干扰 RNA 敲除 DRs 可显著逆转 BV 诱导的细胞生长抑制作用。促凋亡蛋白（caspase-3 和 Bax）的表达同时增加，但 NF-κB 活性和 Bcl-2 的表达受到抑制。肿瘤坏死因子（TNF）样凋亡弱诱导剂、TNF 相关凋亡诱导配体、多西他赛和顺铂与 BV 的联合治疗可协同抑制 A549 和 NCI-H460 肺癌细胞的生长，进一步下调 NF-κB 活性。这些结果表明，BV 通过增强 DR3 表达和抑制 NF-κB 通路诱导肺癌细胞的凋亡性细胞死亡。
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