Dinaciclib prolongs survival in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) transgenic murine models of pancreatic ductal adenocarcinoma

Jia Yang; Su Hu; Junjie Shangguan; Aydin Eresen; Yu Li; Quanhong Ma; Vahid Yaghmai; Al B. Benson; Zhuoli Zhang

Dinaciclib prolongs survival in the LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) transgenic murine models of pancreatic ductal adenocarcinoma

Jia Yang, Su Hu, Junjie Shangguan, Aydin Eresen, Yu Li, Quanhong Ma, Vahid Yaghmai, Al B. Benson, Zhuoli Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8⁺ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.

Original language	English (US)
Pages (from-to)	1031-1043
Number of pages	13
Journal	American Journal of Translational Research
Volume	12
Issue number	3
State	Published - 2020

Funding

The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the Na- tional Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the National Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center.

Keywords

Apoptosis
Dinaciclib
Magnetic resonance imaging
Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

Molecular Medicine
Clinical Biochemistry
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@article{00de110bb55442269bdbe0bccb465d41,

title = "Dinaciclib prolongs survival in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) transgenic murine models of pancreatic ductal adenocarcinoma",

abstract = "Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8+ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.",

keywords = "Apoptosis, Dinaciclib, Magnetic resonance imaging, Pancreatic ductal adenocarcinoma",

author = "Jia Yang and Su Hu and Junjie Shangguan and Aydin Eresen and Yu Li and Quanhong Ma and Vahid Yaghmai and Benson, {Al B.} and Zhuoli Zhang",

note = "Funding Information: The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the Na- tional Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. Funding Information: The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the National Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2020 E-Century Publishing Corporation. All rights reserved.",

year = "2020",

language = "English (US)",

volume = "12",

pages = "1031--1043",

journal = "American Journal of Translational Research",

issn = "1943-8141",

publisher = "e-Century Publishing Corporation",

number = "3",

}

TY - JOUR

T1 - Dinaciclib prolongs survival in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) transgenic murine models of pancreatic ductal adenocarcinoma

AU - Yang, Jia

AU - Hu, Su

AU - Shangguan, Junjie

AU - Eresen, Aydin

AU - Li, Yu

AU - Ma, Quanhong

AU - Yaghmai, Vahid

AU - Benson, Al B.

AU - Zhang, Zhuoli

N1 - Funding Information: The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the Na- tional Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. Funding Information: The authors thank the staff of the Pathology Core Facility at the Northwestern University for histology analysis. We also thank Matteo Figini for assistance with the MR imaging studies. This study was supported by the National Cancer Institute (grants R01CA209886, R01CA196967), by 2019 Harold E. Eisenberg Foundation Scholar Award and by the Fishel Fellowship Award at the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: © 2020 E-Century Publishing Corporation. All rights reserved.

PY - 2020

Y1 - 2020

N2 - Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8+ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.

AB - Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8+ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.

KW - Apoptosis

KW - Dinaciclib

KW - Magnetic resonance imaging

KW - Pancreatic ductal adenocarcinoma

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M3 - Article

AN - SCOPUS:85082798271

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VL - 12

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EP - 1043

JO - American Journal of Translational Research

JF - American Journal of Translational Research

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