title: How liposomal Cisplatin overcomes chemoresistance in ovarian tumour cells.
abstract: The frequent development of cellular resistance to cisplatin in cancer patients is a serious limitation for clinical drug therapy. However, cisplatin resistance is incompletely understood. We have shown that cisplatin-resistant A2780 ovarian cancer cells (A2780cis) can efficiently be eliminated by liposomal cisplatin, which displayed similar cytotoxicity towards both A2780 and A2780cis cells. This may, at least in part, be related to a higher intracellular accumulation of the drug within the resistant cells after liposomal entry. However, the superior cytotoxicity of the liposomal drug was not reflected by DNA platination. This suggests a more complex mode of action of liposomal cisplatin, most likely affecting different signaling pathways. To gain insight into the resistance gene signature, a whole-genome gene expression analysis was performed for A2780cis cells, untreated or treated with half-minimal inhibitory concentration (IC50) of free and liposomal cisplatin. Strong differences in the functional networks affected by free and liposomal cisplatin became evident. p53 was identified as a key factor directing differences in the apoptotic processes. While free cisplatin induced the intrinsic pathway of apoptosis, liposomal cisplatin induced expression of genes of DNA damage pathways and of the extrinsic pathway of apoptosis. These predictions from gene expression data were confirmed at the protein and function level. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal cisplatin as a promising strategy for the treatment of cisplatin-resistant ovarian carcinoma.
authors.affiliation: M.Sc., Institute of Pharmacy, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. dastoelt@uni-bonn.de.
authors.forename: Daniel Philipp
authors.initials: DP
authors.lastname: Stölting
authors.forename: Michaela
authors.initials: M
authors.lastname: Borrmann
authors.forename: Martin
authors.initials: M
authors.lastname: Koch
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Royer
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D020169:Caspases; D002945:Cisplatin
keywords: Apoptosis; chemoresistance; cisplatin; liposomes; ovarian carcinoma