Abstract
ABSTRACT: Gemcitabine is the standard-of-care for chemotherapy in patients with pancreatic adenocarcinoma and it can directly incorporate into DNA or inhibit ribonucleotide reductase to prevent DNA replication and, thus, tumor cell growth. Most pancreatic tumors, however, develop resistance to gemcitabine. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is significantly elevated in human pancreatic cancer. In this study, we show that Plk1 is required for the G1/S transition and that inhibition of Plk1 significantly reduces the DNA synthesis rate in human pancreatic cancer cells. Furthermore, the combined effect of a specific Plk1 inhibitor GSK461364A with gemcitabine was examined. We show that inhibition of Plk1 significantly potentiates the anti-neoplastic activity of gemcitabine in both cultured pancreatic cancer cells and Panc1-derived orthotopic pancreatic cancer xenograft tumors. Overall, our study demonstrates that co-targeting Plk1 can significantly enhance the efficacy of gemcitabine, offering a promising new therapeutic option for the treatment of gemcitabine-resistant human pancreatic cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 711-719 |
| Number of pages | 9 |
| Journal | Cell Cycle |
| Volume | 15 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 3 2016 |
Bibliographical note
Funding Information:This work was supported by NIH grant R01 CA157429 (X.L.), NIH grant R01 CA124586 (S.F.K), NIH grant R01 AR059130 (N.A.), and ACS grant RSG-13-073 (X.L.). Xenograft data were acquired by a Purdue Center for Cancer Research facility supported by P30 CA023168.
Publisher Copyright:
© 2016 Taylor & Francis Group, LLC.
Keywords
- Plk1
- combination therapy
- gemcitabine resistance
- pancreatic cancer
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology
