title: Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer.
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.
authors.affiliation: a Department of Biochemistry , Purdue University , West Lafayette , IN , USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: a Department of Biochemistry , Purdue University , West Lafayette , IN , USA.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Wang
authors.affiliation: b Department of Biological Science , Purdue University , West Lafayette , IN , USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Schweickert
authors.affiliation: b Department of Biological Science , Purdue University , West Lafayette , IN , USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Karki
authors.affiliation: b Department of Biological Science , Purdue University , West Lafayette , IN , USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: b Department of Biological Science , Purdue University , West Lafayette , IN , USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: c Department of Dermatology , University of Wisconsin , Madison , WI , USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: b Department of Biological Science , Purdue University , West Lafayette , IN , USA.|d Center for Cancer Research, Purdue University , West Lafayette , IN , USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: a Department of Biochemistry , Purdue University , West Lafayette , IN , USA.|d Center for Cancer Research, Purdue University , West Lafayette , IN , USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016196:S Phase; D013876:Thiophenes / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1; C544835:GSK 461364A
keywords: Plk1; combination therapy; gemcitabine resistance; pancreatic cancer