PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma.
PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma.
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DOI：
10.1038/s41598-017-02162-9
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发表时间：
2017-05-15
影响因子：
4.6
通讯作者：
Tachibana H
中科院分区：
文献类型：
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作者：
Kumazoe M;Takai M;Hiroi S;Takeuchi C;Yamanouchi M;Nojiri T;Onda H;Bae J;Huang Y;Takamatsu K;Yamashita S;Yamada S;Kangawa K;Takahashi T;Tanaka H;Tachibana H
在大多数胰腺导管腺癌（PDAC）患者中观察到化疗后复发。最近的研究表明，癌症干细胞（CSCs）可能参与PDAC复发和转移。然而，靶向胰腺CSC的有效方法仍有待建立。在这里，我们表明，在癌细胞过度表达的67 kDa层粘连蛋白受体（67 LR）依赖性环GMP（cGMP）诱导剂，表没食子儿茶素-3-O-没食子酸酯（EGCG）和磷酸二酯酶3（PDE 3）抑制剂的组合显着抑制叉头盒O3和CD 44轴，这是必不可少的CSC性能的PDAC。我们证实，EGCG和PDE 3抑制剂的组合强烈抑制体内肿瘤形成和肝转移。我们还发现，合成的EGCG类似物能够诱导强烈的cGMP生产大幅抑制CSC性能的PDAC和延长生存期在体内。总之，EGCG和PDE 3抑制剂作为强cGMP诱导剂的联合治疗可能是根除PDAC CSC的潜在治疗候选者。
Recurrence following chemotherapy is observed in the majority of patients with pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that cancer stem cells (CSCs) may be involved in PDAC recurrence and metastasis. However, an efficient approach to targeting pancreatic CSCs remains to be established. Here we show that in cancer cells overexpressing the 67-kDa laminin receptor (67LR)-dependent cyclic GMP (cGMP) inducer, epigallocatechin-3-O-gallate (EGCG) and a phosphodiesterase 3 (PDE3) inhibitor in combination significantly suppressed the Forkhead box O3 and CD44 axis, which is indispensable for the CSC properties of PDAC. We confirmed that the EGCG and PDE3 inhibitor in combination strongly suppressed tumour formation and liver metastasis in vivo. We also found that a synthesized EGCG analog capable of inducing strong cGMP production drastically suppressed the CSC properties of PDAC and extended the survival period in vivo. In conclusion, the combination treatment of EGCG and a PDE3 inhibitor as a strong cGMP inducer could be a potential treatment candidate for the eradication of CSCs of PDAC.