title: Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate.
abstract: Cisplatin is used in treatment of several types of cancer, including epithelial ovarian carcinoma (EOC). In order to mimic clinical treatment and to investigate longterm effects of cisplatin in surviving cancer cells, two EOC cell lines were repeatedly treated with low doses. In the SKOV-3 cell line originating from malignant ascites, but not in A2780 cells from a primary tumor, this led to emergence of a stable population (SKOV-3-R) which in the absence of cisplatin showed increased motility, epithelial-mesenchymal transition (EMT) and expression of cancer stem cell markers CD117, CD44 and ALDH1. Accordingly, the cells formed self-renewing spheres in serum-free stem cell medium. Despite upregulation of mitochondrial mass and cytochrome c, and no upregulation of Bcl-2/Bcl-xL, SKOV-3-R were multiresistant to antineoplastic drugs. Cancer stem cells, or tumor-initiating cells (TICs) are highly chemoresistant and are believed to cause relapse into disseminated and resistant EOC. Our second aim was therefore to target resistance in these TIC-like cells. Resistance could be correlated with upregulation of hexokinase-II and VDAC, which are known to form a survival-promoting mitochondrial complex. The cells were thus sensitive to 3-bromopyruvate, which dissociates hexokinase-II from this complex, and were particularly sensitive to combination treatment with cisplatin at doses down to 0.1 x IC 50. 3-bromopyruvate might thus be of use in targeting the especially aggressive TIC populations.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: My
authors.initials: M
authors.lastname: Wintzell
authors.forename: Lina
authors.initials: L
authors.lastname: Löfstedt
authors.forename: Joel
authors.initials: J
authors.lastname: Johansson
authors.forename: Anne B
authors.initials: AB
authors.lastname: Pedersen
authors.forename: Jonas
authors.initials: J
authors.lastname: Fuxe
authors.forename: Maria
authors.initials: M
authors.lastname: Shoshan
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001201:Ascites / Q000188:drug therapy; D014408:Biomarkers, Tumor; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D014411:Neoplastic Stem Cells; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D050697:Retinal Dehydrogenase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D011773:Pyruvates; C017092:bromopyruvate; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D002945:Cisplatin