FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

BMC Cancer
Dannel YeoMehrdad Nikfarjam

Abstract

Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1α expression were also inhibited. FRAX597 inhibited pancre...Continue Reading

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Citations

Jun 11, 2016·Cell Death and Differentiation·M KimE-H Jho
Sep 23, 2016·Expert Opinion on Therapeutic Targets·Sankar JagadeeshanSuresh K Rayala
Jan 22, 2017·International Journal of Cancer. Journal International Du Cancer·Dannel YeoMehrdad Nikfarjam
Mar 30, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xing-Hua XiaoLi-Xia Xiong
Feb 2, 2020·BMC Cancer·Palloma Porto AlmeidaLeandro Martins de Freitas
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Apr 3, 2021·Frontiers in Cell and Developmental Biology·Hui LiuZigang Dong

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Methods Mentioned

BETA
transfection

Software Mentioned

SPSS
Sigmaplot
Multigauge
MATLAB
CalcuSyn

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