title: Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells.
abstract: Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.
authors.affiliation: Graduate School of Medical Science and Engineering, South Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.forename: Honsoul
authors.initials: H
authors.lastname: Kim
authors.forename: Da-Hye
authors.initials: DH
authors.lastname: Lee
authors.forename: Tae-shin
authors.initials: TS
authors.lastname: Kim
authors.forename: Tackhoon
authors.initials: T
authors.lastname: Kim
authors.forename: Chaeuk
authors.initials: C
authors.lastname: Chung
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D060888:Real-Time Polymerase Chain Reaction; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram; D000093542:Gemcitabine