title: Proteomic strategy for probing complementary lethality of kinase inhibitors against pancreatic cancer.
abstract: In the present study, proteomic analysis was performed to discover combinational molecular targets for therapy and chemoresistance by comparing differential protein expression from Panc-1 cells treated with FDA-approved drugs such as sunitinib, imatinib mesylate, dasatinib, and PD184352. A total of 4041 proteins were identified in the combined data from all of the treatment groups by nano-electrospray ultra-performance LC and MS/MS analysis. Most of the proteins with significant changes are involved in apoptosis, cytoskeletal remodeling, and epithelial-to-mesenchymal transition. These processes are associated with increased chemoresistance and progression of pancreatic cancer. Among the differentially expressed proteins, heme oxygenase-1 (HO-1) was found in the sunitinib and imatinib mesylate treatment groups, which possibly acts as a specific target for synthetic lethality in combinational treatment. HO-1 was found to play a key role in sensitizing the chemoresistant Panc-1 cell line to drug therapy. Viability was significantly decreased in Panc-1 cells cotreated with sunitinib and imatinib mesylate at low doses, compared to those treated with sunitinib or imatinib mesylate alone. The results suggest that induction of chemosensitization by manipulating specific molecular targets can potentiate synergistic chemotherapeutic effects at lower, better tolerated doses, and in turn reduce the toxicity of multidrug treatment of pancreatic cancer.
authors.affiliation: Proteomics and Mass Spectrometry Research Laboratory, Carolinas HealthCare System, Charlotte, NC, USA.
authors.forename: Jin-Gyun
authors.initials: JG
authors.lastname: Lee
authors.forename: Kimberly Q
authors.initials: KQ
authors.lastname: McKinney
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Mougeot
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Sun-Il
authors.initials: SI
authors.lastname: Hwang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020543:Proteome / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D000077210:Sunitinib; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D000068877:Imatinib Mesylate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000069439:Dasatinib; D000077210:Sunitinib
keywords: Biomedicine; Chemoresistance; Complementary lethality; Heme oxygenase-1; Pancreatic cancer; Tyrosine kinase inhibitors