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首页> 外文期刊>Apoptosis >Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway
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Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway

机译：布法地内酯化合物通过抑制STAT3 / Mcl-1途径使人乳腺癌细胞对TRAIL诱导的细胞凋亡敏感

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摘要

The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone-associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL.
机译：死亡受体配体TRAIL被认为是癌症治疗的有前途的候选者，因为它对恶性细胞具有优先毒性。然而，其抗药性受到许多耐药机制的挑战。因此，需要可以克服抗性以增强TRAIL的治疗功效的药物。在当前的研究中，我们发现从中药ChanSu分离得到的丁二烯内酯的关键成员蟾蜍灵，蟾蜍他灵和gamabufotalin可以显着增强人乳腺癌细胞的功能，使其具有不同的ER-α状态，从而诱导TRAIL凋亡，这通过增强膜联蛋白来证明V / FITC阳性细胞（凋亡细胞），细胞质组蛋白相关的DNA片段，膜通透性转变（MPT），胱天蛋白酶激活和PARP裂解。进一步的机理研究表明，蟾蜍灵能够显着降低Mcl-1表达，并适度降低Bcl-XL表达水平。这些抗凋亡蛋白的下调与转录因子STAT3激活的抑制密切相关。 Mcl-1方法的敲低或过表达证实了bubulin与TRAIL结合后下调Mcl-1在增强作用中的重要结果。我们的发现首次提供了有力的证据，表明丁二烯内酯化合物具有作为新型TRAIL敏化剂的潜力。

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