title: Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance.
abstract: Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3). Whereas PDIA1 knockdown led to increased cytotoxicity in resistant A2780cis cells, PDIA3 knockdown showed no influence on cytotoxicity. Coincubation with propynoic acid carbamoyl methyl amide 31 (PACMA31), a PDIA1 inhibitor, resensitized A2780cis cells to cisplatin treatment. Determination of the combination index revealed that the combination of cisplatin and PACMA31 acts synergistically. Our results warrant further evaluation of PDIA1 as promising target for chemotherapy, and its inhibition by PACMA31 as a new therapeutic approach.
authors.affiliation: University of Bonn, Institute of Pharmacy, Department of Clinical Pharmacy, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kullmann
authors.affiliation: University of Bonn, Institute of Pharmacy, Department of Clinical Pharmacy, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Ganna V
authors.initials: GV
authors.lastname: Kalayda
authors.affiliation: University of Bonn, Institute of Pharmacy, Department of Clinical Pharmacy, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Hellwig
authors.affiliation: University of Cologne, Cologne Biocenter, Zülpicherstraße 47b, 50674 Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kotz
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Hilger
authors.affiliation: University of Cologne, Cologne Biocenter, Zülpicherstraße 47b, 50674 Cologne, Germany; IUF-Leibniz Research Institute for Environmental Medicine, Aufm Hennekamp 50, 40225 Düsseldorf, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Metzger
authors.affiliation: University of Bonn, Institute of Pharmacy, Department of Clinical Pharmacy, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: u.jaehde@uni-bonn.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011393:Procollagen-Proline Dioxygenase; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; D002945:Cisplatin
keywords: Cisplatin; PACMA31; PDIA1; PDIA3; Resistance; SiRNA knockdown