PDE3 inhibitor and EGCG combination treatment suppress cancer stem cell properties in pancreatic ductal adenocarcinoma

Scientific Reports
Motofumi KumazoeHirofumi Tachibana

Abstract

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.

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Citations

Jul 15, 2017·Expert Review of Gastroenterology & Hepatology·Yong Seok KimKi Baik Hahm
Aug 1, 2018·Current Drug Targets·E Paul CherniackHeather F Lee
Mar 13, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Liu-Xiang WangXin-Qiang Zheng
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Nov 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Motofumi KumazoeHirofumi Tachibana
Mar 27, 2018·European Journal of Medicinal Chemistry·Ting PengJianyou Shi
Jun 9, 2021·Journal of Natural Medicines·Motofumi KumazoeHirofumi Tachibana
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aline YammineNorbert Latruffe
Jul 18, 2021·Seminars in Cancer Biology·Man ChuZhi-Wei Wang
Aug 29, 2021·Cancer Metastasis Reviews·Kalyani PatilShahab Uddin

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Methods Mentioned

BETA
xenograft
flow cytometry
dissemination
FCS

Software Mentioned

GraphPad Prism
GraphPad

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