title: Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells.
abstract: Chemotherapy often fails to eradicate cancer stem cells (CSCs) that drive cancer recurrence. In fact, the treated tumors often contain a higher frequency of chemo-resistant CSCs. It is thought that CSC formation is supported by exposure of cancer cells to sub-cytotoxic chemotherapy doses as a result of poor drug penetration in epithelial tumors. We have shown that low-dos cisplatin triggers the transdifferentiation of ovarian cancer cells into CSCs through processes that are also involved in the generation and maintenance of induced pluripotent stem (iPS) cells. Considering similarities between CSCs and iPS cells, we screened a library of 60 synthetic small-molecule compounds, designed to influence EMT/MET signaling in iPS cells on primary ovarian cancer cells. Using a Nanog reporter system we identified a series of compounds capable of blocking the cisplatin triggered formation of CSCs. We then focused on compound GHDM-1515, a drug that acts on pathways that regulate histone demethylases. We demonstrated that co-treatment of primary ovarian cancer cells with GHDM-1515 significantly increased cisplatin induced apoptosis, specifically apoptosis of CSCs. GHDM-1515 inhibited EMT and the cisplatin-induced formation of CSCs. This suggests that GHDM-1515 can sensitize ovarian cancer cells to low-dose cisplatin and potentially enhance the efficacy of cisplatin chemotherapy.
authors: a University of Washington, Division of Medical Genetics , Seattle WA , USA.
authors: Kamola
authors: K
authors: Saydaminova
authors: a University of Washington, Division of Medical Genetics , Seattle WA , USA.|d Department of Medical Biochemistry and Biophysics , Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute , Solna , Sweden.
authors: Robert
authors: R
authors: Strauss
authors: c Gladstone Institute, UCSF , San Francisco , CA.
authors: Min
authors: M
authors: Xie
authors: b Danish Cancer Society Research Center , Genome Integrity Unit and Center for Genotoxic Stress Research , Copenhagen , Denmark.|d Department of Medical Biochemistry and Biophysics , Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute , Solna , Sweden.
authors: Jiri
authors: J
authors: Bartek
authors: a University of Washington, Division of Medical Genetics , Seattle WA , USA.
authors: Maximilian
authors: M
authors: Richter
authors: a University of Washington, Division of Medical Genetics , Seattle WA , USA.
authors: Ruan
authors: R
authors: van Rensburg
authors: e Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors: Charles
authors: C
authors: Drescher
authors: f University Witten/Herdecke , Witten , Germany.
authors: Anja
authors: A
authors: Ehrhardt
authors: e Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors: Sheng
authors: S
authors: Ding
authors: a University of Washington, Division of Medical Genetics , Seattle WA , USA.|g University of Washington , Department of Pathology , Seattle , WA , USA.
authors: André
authors: A
authors: Lieber
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D002945:Cisplatin
keywords: Cisplatin; epithelial-to-mesenchymal transition; ovarian cancer; resistance