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*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1031-1043
Number of pages13
JournalAmerican Journal of Translational Research
Volume12
Issue number3
StatePublished - Jan 1 2020

Keywords

  • Apoptosis
  • Dinaciclib
  • Magnetic resonance imaging
  • Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

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