Zoledronic acid re‑sensitises gefitinib‑resistant lung cancer cells by inhibiting the JAK/STAT3 signalling pathway and reversing epithelial‑mesenchymal transition.
Zoledronic acid re‑sensitises gefitinib‑resistant lung cancer cells by inhibiting the JAK/STAT3 signalling pathway and reversing epithelial‑mesenchymal transition.
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唑来膦酸通过抑制 JAK/STAT3 信号通路和逆转上皮-间质转化，使吉非替尼耐药肺癌细胞重新变得敏感
DOI：
10.3892/or.2020.7881
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发表时间：
2021-03
期刊：
影响因子：
4.2
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Yang X;Gao Y;Liu Q;Wan L;Liu H;Bian W;Du Y;Huang C
研究表明，抑制JAK/STAT3通路和上皮-间充质转化(EMT)可能会逆转非小细胞肺癌(NSCLC)细胞对吉非替尼的耐药性。唑来膦酸(ZA)注射剂用于治疗和预防多种形式的骨质疏松症、高钙血症和恶性肿瘤骨转移相关并发症。临床研究表明，ZA可能具有抗肿瘤作用，延缓NSCLC的进展。在本研究中，我们通过抑制JAK/STAT3信号通路和EMT逆转，在体内外研究了ZA联合吉非替尼是否能使NSCLC细胞对吉非替尼重新敏感。结果表明，ZA能有效提高耐吉非替尼肺癌细胞对吉非替尼的敏感性。ZA可降低H1975和HCC827GR细胞中JAK/STAT3信号的激活，并逆转EMT。此外，在ZA处理的Gefitinib耐药细胞系中加入IL-6可消除ZA的作用，并恢复细胞对酪氨酸激酶抑制剂的耐药性。最后，基于ZA的联合治疗有效地抑制了吉非替尼耐药癌细胞来源的异种移植瘤的生长，这与抑制JAK/STAT3信号通路和逆转EMT有关。综上所述，ZA通过抑制JAK/STAT3信号通路和EMT逆转，使耐吉非替尼的肺癌细胞重新增敏。ZA联合吉非替尼可能是逆转吉非替尼耐药、延长非小细胞肺癌患者生存时间的一种有前景的治疗策略。
Studies have shown that suppression of both the JAK/STAT3 pathway and epithelial-mesenchymal transition (EMT) may overturn the resistance of non-small cell lung cancer (NSCLC) cells to gefitinib. Zoledronic acid (ZA) injection is used to treat and prevent multiple forms of osteoporosis, hypercalcemia and bone metastasis-related complications of malignancy. Clinical research has shown that ZA may exert antitumour effects and delay the progression of NSCLC. In the present study, we investigated whether ZA combined with gefitinib could re-sensitise NSCLC cells to gefitinib in vitro and in vivo through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The results revealed that ZA potently increased the sensitivity of gefitinib-resistant lung cancer cells to gefitinib. ZA decreased activation of JAK/STAT3 signalling and reversed EMT in the H1975 and HCC827GR cell lines. Furthermore, addition of IL-6 to ZA-pretreated gefitinib-resistant cell lines abrogated the effect of ZA and restored the cellular resistance to tyrosine kinase inhibitors. Finally, ZA-based combinatorial therapy effectively inhibited the growth of xenografts derived from gefitinib-resistant cancer cells, which was correlated with the inhibition of the JAK/STAT3 signalling pathway and EMT reversal. In conclusion, ZA re-sensitised gefitinib-resistant lung cancer cells through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The combination of ZA and gefitinib may be a promising therapeutic strategy to reverse gefitinib resistance and prolong the survival of patients with NSCLC.
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影响因子：
8.8
作者：
Scott, HR;McMillan, DC;Crilly, A;McArdle, CS;Milroy, R
通讯作者：
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作者：
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作者：
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