Sensitization of Pancreatic Cancer Stem Cells to Gemcitabine by Chk1 Inhibition

Autor: Venkatasubbaiah A. Venkatesha, Leslie A. Parsels, Joshua D. Parsels, Lili Zhao, Sonya D. Zabludoff, Diane M. Simeone, Jonathan Maybaum, Theodore S. Lawrence, Meredith A. Morgan
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: Neoplasia: An International Journal for Oncology Research, Vol 14, Iss 6, Pp 519-525 (2012)
Druh dokumentu: article
ISSN: 1476-5586
1522-8002
42448492
DOI: 10.1593/neo.12538
Popis: Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 inhibition would sensitize pancreatic cancer stem cells to gemcitabine. We tested this hypothesis by using two patient-derived xenograft models (designated J and F) and the pancreatic cancer stem cell markers CD24, CD44, and ESA. We determined the percentage of marker-positive cells and their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine and the Chk1 inhibitor, AZD7762. We found that marker-positive cells were significantly reduced by the combination of gemcitabine and AZD7762. In addition, secondary tumor initiation was significantly delayed in response to primary tumor treatment with gemcitabine + AZD7762 compared with control, gemcitabine, or AZD7762 alone. Furthermore, for the same number of stem cells implanted from gemcitabine- versus gemcitabine + AZD7762-treated primary tumors, secondary tumor initiation at 10 weeks was 83% versus 43%, respectively. We also found that pS345 Chk1, which is a measure of DNA damage, was induced in marker-positive cells but not in the marker-negative cells. These data demonstrate that Chk1 inhibition in combination with gemcitabine reduces both the percentage and the tumor-initiating capacity of pancreatic cancer stem cells. Furthermore, the finding that the Chk1-mediated DNA damage response was greater in stem cells than in non-stem cells suggests that Chk1 inhibition may selectively sensitize pancreatic cancer stem cells to gemcitabine, thus making Chk1 a potential therapeutic target for improving pancreatic cancer therapy.
Databáze: Directory of Open Access Journals
Externí odkaz: