Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines.
Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines.
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DOI：
10.3892/ijo.2015.3237
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发表时间：
2016-01
影响因子：
5.2
通讯作者：
Miyazawa K
中科院分区：
文献类型：
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作者：
Mukai S;Moriya S;Hiramoto M;Kazama H;Kokuba H;Che XF;Yokoyama T;Sakamoto S;Sugawara A;Sunazuka T;Ōmura S;Handa H;Itoi T;Miyazawa K
胰腺癌是最难治疗的癌症类型之一，因为它的高死亡率归因于化疗耐药性。我们以前报道过，吉非替尼（GEF）和克拉霉素（CAM）联合治疗导致非小细胞肺癌细胞系中GEF沿着内质网（ER）应激负荷的细胞毒性增强。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）如GEF以促存活作用诱导自噬，而CAM抑制各种细胞系中的自噬通量。因此，明显的GEF诱导的细胞毒性似乎取决于自噬抑制的功效。在本研究中，我们比较了CAM，阿奇霉素（AZM）和EM 900，一种新的12元非抗生素大环内酯类药物之间的自噬抑制作用。然后，我们评估了增强GEF诱导的对胰腺癌细胞系BxPC-3和PANC-1的细胞毒性作用。自噬通量分析表明，AZM是三种大环内酯类药物中最有效的自噬抑制剂。CAM具有抑制作用，但小于AZM和EM 900。值得注意的是，通过组合大环内酯类来增强GEF诱导的细胞毒性的效果与其有效的自噬抑制很好地相关。然而，这种明显的细胞毒性不是由于细胞凋亡诱导上调，但至少部分介导的坏死性凋亡。我们的数据表明，使用大环内酯类药物作为“化疗增敏剂”的EGFR-TKI治疗胰腺癌患者，以提高非凋亡性肿瘤细胞死亡诱导的可能性。
Pancreatic cancer is one of the most difficult types of cancer to treat because of its high mortality rate due to chemotherapy resistance. We previously reported that combined treatment with gefitinib (GEF) and clarithromycin (CAM) results in enhanced cytotoxicity of GEF along with endoplasmic reticulum (ER) stress loading in non-small cell lung cancer cell lines. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) such as GEF induces autophagy in a pro-survival role, whereas CAM inhibits autophagy flux in various cell lines. Pronounced GEF-induced cytotoxicity therefore appears to depend on the efficacy of autophagy inhibition. In the present study, we compared the effect on autophagy inhibition among such macrolides as CAM, azithromycin (AZM), and EM900, a novel 12-membered non-antibiotic macrolide. We then assessed the enhanced GEF-induced cytotoxic effect on pancreatic cancer cell lines BxPC-3 and PANC-1. Autophagy flux analysis indicated that AZM is the most effective autophagy inhibitor of the three macrolides. CAM exhibits an inhibitory effect but less than AZM and EM900. Notably, the enhancing effect of GEF-induced cytotoxicity by combining macrolides correlated well with their efficient autophagy inhibition. However, this pronounced cytotoxicity was not due to upregulation of apoptosis induction, but was at least partially mediated through necroptosis. Our data suggest the possibility of using macrolides as ‘chemosensitizers’ for EGFR-TKI therapy in pancreatic cancer patients to enhance non-apoptotic tumor cell death induction.